rs374356079

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The ENST00000378587.3(DYNC2LI1):c.943G>A(p.Val315Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000221 in 1,587,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V315V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

DYNC2LI1
ENST00000378587.3 missense

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 4.80

Publications

2 publications found

Variant links:

Genes affected

DYNC2LI1 (HGNC:24595): (dynein cytoplasmic 2 light intermediate chain 1) This gene encodes a protein that is a component of the dynein-2 microtubule motor protein complex that plays a role in the retrograde transport of cargo in primary cilia via the intraflagellar transport system. This gene is ubiquitously expressed and its protein, which localizes to the axoneme and Golgi apparatus, interacts directly with the cytoplasmic dynein 2 heavy chain 1 protein to form part of the multi-protein dynein-2 complex. Mutations in this gene produce defects in the dynein-2 complex which result in several types of ciliopathy including short-rib thoracic dysplasia 15 with polydactyly (SRTD15). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2017]

DYNC2LI1 Gene-Disease associations (from GenCC):

short-rib thoracic dysplasia 15 with polydactyly
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Ellis-van Creveld syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Jeune syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DYNC2LI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-43805247-G-A is Pathogenic according to our data. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-43805247-G-A is described in CliVar as Pathogenic. Clinvar id is 212764.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DYNC2LI1	NM_016008.4 link	c.993+1G>A	splice_donor_variant, intron_variant	Intron 12 of 12	ENST00000260605.12	NP_057092.2	Q8TCX1-1
DYNC2LI1	NM_001348913.2 link	c.996+1G>A	splice_donor_variant, intron_variant	Intron 12 of 13		NP_001335842.1
DYNC2LI1	NM_001348912.2 link	c.993+1G>A	splice_donor_variant, intron_variant	Intron 12 of 13		NP_001335841.1
DYNC2LI1	NM_001193464.2 link	c.996+1G>A	splice_donor_variant, intron_variant	Intron 12 of 12		NP_001180393.1	Q8TCX1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DYNC2LI1	ENST00000378587.3 link	c.943G>A	p.Val315Ile	missense_variant	Exon 11 of 11	1		ENSP00000367850.3	H7BYC8
DYNC2LI1	ENST00000260605.12 link	c.993+1G>A		splice_donor_variant, intron_variant	Intron 12 of 12	1	NM_016008.4	ENSP00000260605.8	Q8TCX1-1
DYNC2LI1	ENST00000605786.5 link	c.996+1G>A		splice_donor_variant, intron_variant	Intron 12 of 12	1		ENSP00000474032.1	Q8TCX1-2
DYNC2LI1	ENST00000482738.1 link	n.*70G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000201

AC:

AN:

248506

AF XY:

0.0000223

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000444

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000237

AC:

AN:

1434956

Hom.:

Cov.:

AF XY:

0.0000182

AC XY:

AN XY:

715496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32834

American (AMR)

AF:

0.0000226

AC:

AN:

44194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25916

East Asian (EAS)

AF:

0.00

AC:

AN:

39428

South Asian (SAS)

AF:

0.00

AC:

AN:

84944

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5562

European-Non Finnish (NFE)

AF:

0.0000303

AC:

AN:

1089284

Other (OTH)

AF:

0.00

AC:

AN:

59470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000200

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 1

Pathogenic:1

David Geffen School of Medicine, University of California, Los Angeles

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Pathogenic:1

Dec 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 12 of the DYNC2LI1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs374356079, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with short rib polydactyly syndrome (PMID: 26077881). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 212764). Studies have shown that disruption of this splice site alters DYNC2LI1 gene expression (PMID: 26077881). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 26077881). For these reasons, this variant has been classified as Pathogenic. -

Short-rib thoracic dysplasia 15 with polydactyly

Pathogenic:1

Jun 16, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

PhyloP100

4.8

GERP RS

4.9

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.92

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over