rs585692

Positions:

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

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001080463.2(DYNC2H1):​c.5718C>A​(p.Thr1906=) 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:10
• Conservation: PhyloP100: 0.509

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 -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 id is 167011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103176278-C-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.5718C>A	p.Thr1906=	synonymous_variant	37/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.5718C>A	p.Thr1906=	synonymous_variant	37/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.5718C>A	p.Thr1906=	synonymous_variant	37/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.5718C>A	p.Thr1906=	synonymous_variant	37/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+41859C>A		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*3263C>A		3_prime_UTR_variant, NMD_transcript_variant	35/51

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

GnomAD3 exomes AF: 0.926 AC: 137631 AN: 148700 Hom.: 63844 AF XY: 0.921 AC XY: 72449 AN XY: 78652

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 SAS exome AF: 0.879

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

Gnomad4 AFR exome AF: 0.981

Gnomad4 AMR exome AF: 0.959

Gnomad4 ASJ exome AF: 0.912

Gnomad4 EAS exome AF: 0.855

Gnomad4 SAS exome AF: 0.880

Gnomad4 FIN exome AF: 0.969

Gnomad4 NFE exome AF: 0.925

Gnomad4 OTH exome AF: 0.924

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

Gnomad4 AFR AF: 0.980

Gnomad4 AMR AF: 0.942

Gnomad4 ASJ AF: 0.911

Gnomad4 EAS AF: 0.873

Gnomad4 SAS AF: 0.881

Gnomad4 FIN AF: 0.976

Gnomad4 NFE AF: 0.926

Gnomad4 OTH AF: 0.938

Alfa AF: 0.931 Hom.: 40609

Bravo AF: 0.943

Asia WGS AF: 0.853 AC: 2964 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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: Frequency -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Eurofins Ntd Llc (ga)	Apr 27, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 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. -

Jeune thoracic dystrophy Benign:2

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

Asphyxiating thoracic dystrophy 3 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	1.8
DANN	Benign	0.60

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: rs585692; hg19: chr11-103047007;