rs589623

Positions:

• chr11-103211861-G-A

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.8612G>A​(p.Arg2871Gln) variant causes a missense change. The variant allele was found at a frequency of 0.793 in 1,521,494 control chromosomes in the GnomAD database, including 480,082 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (43913 hom., cov: 32)
  • Exomes 𝑓: 0.80 (436169 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.41

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 (MetaRNN=2.285225E-6).
• BP6: Variant 11-103211861-G-A is Benign according to our data. Variant chr11-103211861-G-A is described in ClinVar as [Benign]. Clinvar id is 302073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103211861-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.8612G>A	p.Arg2871Gln	missense_variant	54/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.8612G>A	p.Arg2871Gln	missense_variant	54/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.8612G>A	p.Arg2871Gln	missense_variant	54/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.8612G>A	p.Arg2871Gln	missense_variant	54/89	1	NM_001377.3	ENSP00000364887	P3
DYNC2H1	ENST00000334267.11	c.2205+77442G>A		intron_variant		1		ENSP00000334021
DYNC2H1	ENST00000533027.1	n.212G>A		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114756 AN: 151872 Hom.: 43869 Cov.: 32

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.899

Gnomad AMR AF: 0.835

Gnomad ASJ AF: 0.846

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.772

Gnomad FIN AF: 0.790

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.779

GnomAD3 exomes AF: 0.794 AC: 120667 AN: 152026 Hom.: 48240 AF XY: 0.795 AC XY: 63767 AN XY: 80228

Gnomad AFR exome AF: 0.603

Gnomad AMR exome AF: 0.848

Gnomad ASJ exome AF: 0.839

Gnomad EAS exome AF: 0.767

Gnomad SAS exome AF: 0.765

Gnomad FIN exome AF: 0.802

Gnomad NFE exome AF: 0.805

Gnomad OTH exome AF: 0.806

GnomAD4 exome AF: 0.797 AC: 1091217 AN: 1369504 Hom.: 436169 Cov.: 32 AF XY: 0.796 AC XY: 537112 AN XY: 674624

Gnomad4 AFR exome AF: 0.610

Gnomad4 AMR exome AF: 0.847

Gnomad4 ASJ exome AF: 0.848

Gnomad4 EAS exome AF: 0.731

Gnomad4 SAS exome AF: 0.766

Gnomad4 FIN exome AF: 0.802

Gnomad4 NFE exome AF: 0.804

Gnomad4 OTH exome AF: 0.787

GnomAD4 genome AF: 0.756 AC: 114855 AN: 151990 Hom.: 43913 Cov.: 32 AF XY: 0.756 AC XY: 56184 AN XY: 74278

Gnomad4 AFR AF: 0.621

Gnomad4 AMR AF: 0.835

Gnomad4 ASJ AF: 0.846

Gnomad4 EAS AF: 0.777

Gnomad4 SAS AF: 0.774

Gnomad4 FIN AF: 0.790

Gnomad4 NFE AF: 0.804

Gnomad4 OTH AF: 0.779

Alfa AF: 0.799 Hom.: 101576

Bravo AF: 0.754

TwinsUK AF: 0.803 AC: 2979

ALSPAC AF: 0.804 AC: 3099

ESP6500AA AF: 0.630 AC: 2258

ESP6500EA AF: 0.810 AC: 6501

ExAC AF: 0.741 AC: 70849

Asia WGS AF: 0.734 AC: 2544 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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 -

Asphyxiating thoracic dystrophy 3 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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	Mendelics	May 28, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Jeune thoracic dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Short rib-polydactyly syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T;T;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	.;T;.;T
MetaRNN	Benign	0.0000023	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N;N;N;N
MutationTaster	Benign	0.00038	P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.7	N;.;.;N
REVEL	Benign	0.099
Sift	Benign	0.23	T;.;.;T
Sift4G	Benign	0.30	T;.;.;T
Polyphen		0.72	P;P;B;B
Vest4		0.049
MPC		0.084
ClinPred		0.017	T
GERP RS		5.8
Varity_R		0.17
gMVP		0.15

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: rs589623; hg19: chr11-103082590; COSMIC: COSV62088525;