Genetic Variant NM_016008.4:c.126G>A (chr2-43776899-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_016008.4(DYNC2LI1):c.126G>A(p.Gly42Gly) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000000786 in 1,272,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G42G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

DYNC2LI1
NM_016008.4 splice_region, synonymous

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.01

Publications

0 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: Labcorp Genetics (formerly Invitae), G2P
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 6 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. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016008.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DYNC2LI1	NM_016008.4	MANE Select	c.126G>A	p.Gly42Gly	splice_region synonymous	Exon 2 of 13	NP_057092.2
DYNC2LI1	NM_001348913.2		c.126G>A	p.Gly42Gly	splice_region synonymous	Exon 2 of 14	NP_001335842.1
DYNC2LI1	NM_001348912.2		c.126G>A	p.Gly42Gly	splice_region synonymous	Exon 2 of 14	NP_001335841.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DYNC2LI1	ENST00000260605.12	TSL:1 MANE Select	c.126G>A	p.Gly42Gly	splice_region synonymous	Exon 2 of 13	ENSP00000260605.8	Q8TCX1-1
DYNC2LI1	ENST00000605786.5	TSL:1	c.126G>A	p.Gly42Gly	splice_region synonymous	Exon 2 of 13	ENSP00000474032.1	Q8TCX1-2
DYNC2LI1	ENST00000378587.3	TSL:1	c.75G>A	p.Gly25Gly	splice_region synonymous	Exon 1 of 11	ENSP00000367850.3	H7BYC8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.86e-7

AC:

AN:

1272534

Hom.:

Cov.:

AF XY:

0.00000156

AC XY:

AN XY:

641814

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27714

American (AMR)

AF:

0.00

AC:

AN:

39714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24486

East Asian (EAS)

AF:

0.00

AC:

AN:

38382

South Asian (SAS)

AF:

0.00

AC:

AN:

78014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5330

European-Non Finnish (NFE)

AF:

0.00000105

AC:

AN:

951818

Other (OTH)

AF:

0.00

AC:

AN:

53902

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

6.0

PromoterAI

-0.047

Neutral

(source)

Mutation Taster

=5/95

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.32

Position offset: 0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over