2-43796760-C-T

Position:

chr2-43796760-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The ENST00000260605.12(DYNC2LI1):c.619C>T(p.Arg207Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000521 in 1,613,484 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 (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

DYNC2LI1
ENST00000260605.12 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.95

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-43796760-C-T is Pathogenic according to our data. Variant chr2-43796760-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 253218.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DYNC2LI1	NM_016008.4 linkuse as main transcript	c.619C>T	p.Arg207Ter	stop_gained	8/13	ENST00000260605.12	NP_057092.2
DYNC2LI1	NM_001348913.2 linkuse as main transcript	c.622C>T	p.Arg208Ter	stop_gained	8/14		NP_001335842.1
DYNC2LI1	NM_001348912.2 linkuse as main transcript	c.619C>T	p.Arg207Ter	stop_gained	8/14		NP_001335841.1
DYNC2LI1	NM_001193464.2 linkuse as main transcript	c.622C>T	p.Arg208Ter	stop_gained	8/13		NP_001180393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2LI1	ENST00000260605.12 linkuse as main transcript	c.619C>T	p.Arg207Ter	stop_gained	8/13	1	NM_016008.4	ENSP00000260605	P4	Q8TCX1-1
DYNC2LI1	ENST00000605786.5 linkuse as main transcript	c.622C>T	p.Arg208Ter	stop_gained	8/13	1		ENSP00000474032	A1	Q8TCX1-2
DYNC2LI1	ENST00000378587.3 linkuse as main transcript	c.571C>T	p.Arg191Ter	stop_gained	7/11	1		ENSP00000367850
DYNC2LI1	ENST00000489222.6 linkuse as main transcript	n.575C>T		non_coding_transcript_exon_variant	7/8	3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251090

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1461336

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

726976

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change creates a premature translational stop signal (p.Arg207*) in the DYNC2LI1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYNC2LI1 are known to be pathogenic (PMID: 26077881, 26130459). This variant is present in population databases (rs745930390, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with clinical features of DYNC2LI1-related conditions (PMID: 26130459). This variant is also known as p.Arg208Ter. ClinVar contains an entry for this variant (Variation ID: 253218). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Short-rib thoracic dysplasia 15 with polydactyly

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

A;A

Vest4

0.51

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.45

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.45

Position offset: 35

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over