rs11225584

Positions:

• chr11-103181829-T-C
• chr11-103181829-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080463.2(DYNC2H1):​c.6420T>C​(p.Asn2140=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,595,920 control chromosomes in the GnomAD database, including 11,614 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1019 hom., cov: 31)
  • Exomes 𝑓: 0.12 (10595 hom.)
• Consequence: DYNC2H1 NM_001080463.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.330

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 11-103181829-T-C is Benign according to our data. Variant chr11-103181829-T-C is described in ClinVar as [Benign]. Clinvar id is 302054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103181829-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.6420T>C	p.Asn2140=	synonymous_variant	40/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.6420T>C	p.Asn2140=	synonymous_variant	40/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.6420T>C	p.Asn2140=	synonymous_variant	40/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.6420T>C	p.Asn2140=	synonymous_variant	40/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+47410T>C		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*3965T>C		3_prime_UTR_variant, NMD_transcript_variant	38/51

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16337 AN: 151578 Hom.: 1016 Cov.: 31

Gnomad AFR AF: 0.0766

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.0829

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.115 AC: 26097 AN: 226062 Hom.: 1769 AF XY: 0.119 AC XY: 14537 AN XY: 121974

Gnomad AFR exome AF: 0.0784

Gnomad AMR exome AF: 0.0542

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.217

Gnomad SAS exome AF: 0.158

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.117 AC: 169540 AN: 1444224 Hom.: 10595 Cov.: 31 AF XY: 0.119 AC XY: 85352 AN XY: 717004

Gnomad4 AFR exome AF: 0.0742

Gnomad4 AMR exome AF: 0.0575

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.217

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.114

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.108 AC: 16359 AN: 151696 Hom.: 1019 Cov.: 31 AF XY: 0.109 AC XY: 8093 AN XY: 74130

Gnomad4 AFR AF: 0.0770

Gnomad4 AMR AF: 0.0826

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.214

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.103

Alfa AF: 0.110 Hom.: 1268

Bravo AF: 0.101

Asia WGS AF: 0.165 AC: 575 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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: MAF -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Jeune thoracic dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Asphyxiating thoracic dystrophy 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.8
DANN	Benign	0.46

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: rs11225584; hg19: chr11-103052558; COSMIC: COSV62094382;