rs2566913

Variant names:

• chr11-103358299-T-C
• rs2566913
• NM_001080463.2:c.12117T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001377.3(DYNC2H1):​c.12096T>C​(p.Asp4032Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 1,589,806 control chromosomes in the GnomAD database, including 323,291 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24777 hom., cov: 32)
  • Exomes 𝑓: 0.64 (298514 hom.)
• Consequence: DYNC2H1 NM_001377.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.179

Genes affected

DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 11-103358299-T-C is Benign according to our data. Variant chr11-103358299-T-C is described in ClinVar as [Benign]. Clinvar id is 302117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103358299-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.179 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.12117T>C	p.Asp4039Asp	synonymous_variant	Exon 84 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.12096T>C	p.Asp4032Asp	synonymous_variant	Exon 83 of 89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.12117T>C	p.Asp4039Asp	synonymous_variant	Exon 84 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.12096T>C	p.Asp4032Asp	synonymous_variant	Exon 83 of 89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83387 AN: 151878 Hom.: 24765 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.643

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.580

GnomAD3 exomes AF: 0.619 AC: 134827 AN: 217838 Hom.: 42979 AF XY: 0.617 AC XY: 72089 AN XY: 116846

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.735

Gnomad ASJ exome AF: 0.613

Gnomad EAS exome AF: 0.508

Gnomad SAS exome AF: 0.531

Gnomad FIN exome AF: 0.663

Gnomad NFE exome AF: 0.661

Gnomad OTH exome AF: 0.638

GnomAD4 exome AF: 0.640 AC: 920191 AN: 1437810 Hom.: 298514 Cov.: 37 AF XY: 0.638 AC XY: 454675 AN XY: 712966

Gnomad4 AFR exome AF: 0.276

Gnomad4 AMR exome AF: 0.724

Gnomad4 ASJ exome AF: 0.604

Gnomad4 EAS exome AF: 0.532

Gnomad4 SAS exome AF: 0.530

Gnomad4 FIN exome AF: 0.662

Gnomad4 NFE exome AF: 0.662

Gnomad4 OTH exome AF: 0.608

GnomAD4 genome AF: 0.549 AC: 83427 AN: 151996 Hom.: 24777 Cov.: 32 AF XY: 0.549 AC XY: 40787 AN XY: 74302

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.663

Gnomad4 ASJ AF: 0.608

Gnomad4 EAS AF: 0.512

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.643

Gnomad4 NFE AF: 0.658

Gnomad4 OTH AF: 0.577

Alfa AF: 0.637 Hom.: 40122

Bravo AF: 0.544

Asia WGS AF: 0.533 AC: 1854 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jeune thoracic dystrophy Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Asphyxiating thoracic dystrophy 3 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.9
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2566913; hg19: chr11-103229027; COSMIC: COSV62089585;