rs585692

Variant names:

• chr11-103176278-C-A
• rs585692
• NM_001080463.2:c.5718C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-103176278-C-A
• chr11-103176278-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001080463.2(DYNC2H1):​c.5718C>A​(p.Thr1906Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.926 in 1,541,246 control chromosomes in the GnomAD database, including 661,347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1906T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.94 (67723 hom., cov: 32)
  • Exomes 𝑓: 0.92 (593624 hom.)
• Consequence: DYNC2H1 NM_001080463.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.509
• Publications: 23 publications found

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]

DYNC2H1 Gene-Disease associations (from GenCC):

• asphyxiating thoracic dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 11-103176278-C-A is Benign according to our data. Variant chr11-103176278-C-A is described in ClinVar as Benign. ClinVar VariationId is 167011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.509 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.5718C>A	p.Thr1906Thr	synonymous_variant	Exon 37 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.5718C>A	p.Thr1906Thr	synonymous_variant	Exon 37 of 89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.5718C>A	p.Thr1906Thr	synonymous_variant	Exon 37 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.5718C>A	p.Thr1906Thr	synonymous_variant	Exon 37 of 89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes AF: 0.943 AC: 143403 AN: 152150 Hom.: 67652 Cov.: 32

Gnomad AFR AF: 0.980

Gnomad AMI AF: 0.971

Gnomad AMR AF: 0.942

Gnomad ASJ AF: 0.911

Gnomad EAS AF: 0.873

Gnomad SAS AF: 0.880

Gnomad FIN AF: 0.976

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.926

Gnomad OTH AF: 0.938

GnomAD2 exomes AF: 0.926 AC: 137631 AN: 148700 AF XY: 0.921

Gnomad AFR exome AF: 0.981

Gnomad AMR exome AF: 0.961

Gnomad ASJ exome AF: 0.908

Gnomad EAS exome AF: 0.865

Gnomad FIN exome AF: 0.971

Gnomad NFE exome AF: 0.924

Gnomad OTH exome AF: 0.916

GnomAD4 exome AF: 0.924 AC: 1283516 AN: 1388978 Hom.: 593624 Cov.: 46 AF XY: 0.922 AC XY: 631398 AN XY: 684764

African (AFR) AF: 0.981 AC: 30344 AN: 30930

American (AMR) AF: 0.959 AC: 32701 AN: 34088

Ashkenazi Jewish (ASJ) AF: 0.912 AC: 22837 AN: 25044

East Asian (EAS) AF: 0.855 AC: 29995 AN: 35086

South Asian (SAS) AF: 0.880 AC: 67125 AN: 76270

European-Finnish (FIN) AF: 0.969 AC: 47834 AN: 49386

Middle Eastern (MID) AF: 0.868 AC: 4916 AN: 5666

European-Non Finnish (NFE) AF: 0.925 AC: 994534 AN: 1074886

Other (OTH) AF: 0.924 AC: 53230 AN: 57622

GnomAD4 genome AF: 0.943 AC: 143533 AN: 152268 Hom.: 67723 Cov.: 32 AF XY: 0.942 AC XY: 70140 AN XY: 74432

African (AFR) AF: 0.980 AC: 40749 AN: 41572

American (AMR) AF: 0.942 AC: 14399 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.911 AC: 3163 AN: 3472

East Asian (EAS) AF: 0.873 AC: 4522 AN: 5178

South Asian (SAS) AF: 0.881 AC: 4241 AN: 4814

European-Finnish (FIN) AF: 0.976 AC: 10355 AN: 10614

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.926 AC: 62984 AN: 68018

Other (OTH) AF: 0.938 AC: 1979 AN: 2110

Alfa AF: 0.931 Hom.: 46023

Bravo AF: 0.943

Asia WGS AF: 0.853 AC: 2964 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

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

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

- -

Apr 27, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

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. -

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 -

Jeune thoracic dystrophy Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Asphyxiating thoracic dystrophy 3 Benign:2

Jan 13, 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	-0.27
CADD	Benign	1.8
DANN	Benign	0.60
PhyloP100		0.51
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs585692; hg19: chr11-103047007; COSMIC: COSV108161705;