rs200466720

Positions:

• chr11-103153387-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001080463.2(DYNC2H1):​c.3181C>G​(p.Leu1061Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,553,684 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 1.12

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069162548).
• BP6: Variant 11-103153387-C-G is Benign according to our data. Variant chr11-103153387-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195660.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}. Variant chr11-103153387-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.3181C>G	p.Leu1061Val	missense_variant	22/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.3181C>G	p.Leu1061Val	missense_variant	22/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.3181C>G	p.Leu1061Val	missense_variant	22/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.3181C>G	p.Leu1061Val	missense_variant	22/89	1	NM_001377.3	ENSP00000364887	P3

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 206 AN: 151954 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.000788

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000890 AC: 145 AN: 162892 Hom.: 1 AF XY: 0.000734 AC XY: 63 AN XY: 85888

Gnomad AFR exome AF: 0.000111

Gnomad AMR exome AF: 0.000561

Gnomad ASJ exome AF: 0.00116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00168

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00116 AC: 1625 AN: 1401612 Hom.: 3 Cov.: 31 AF XY: 0.00116 AC XY: 804 AN XY: 691464

Gnomad4 AFR exome AF: 0.000188

Gnomad4 AMR exome AF: 0.000529

Gnomad4 ASJ exome AF: 0.00175

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000637

Gnomad4 FIN exome AF: 0.0000403

Gnomad4 NFE exome AF: 0.00137

Gnomad4 OTH exome AF: 0.000999

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.00112 AC XY: 83 AN XY: 74342

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000787

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00175

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.00144

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00161 AC: 13

ExAC AF: 0.000446 AC: 51

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 22, 2014	- -

Asphyxiating thoracic dystrophy 3 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 11, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 29, 2019

- -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Jeune thoracic dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

DYNC2H1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T;T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;.;D;.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.0069	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	.;M;M;M;M
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.8	.;N;.;.;N
REVEL	Benign	0.12
Sift	Uncertain	0.013	.;D;.;.;D
Sift4G	Uncertain	0.054	.;T;.;.;T
Polyphen		0.43, 0.74	.;B;B;P;P
Vest4		0.52, 0.51
MVP		0.45
MPC		0.14
ClinPred		0.016	T
GERP RS		2.7
Varity_R		0.11
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs200466720; hg19: chr11-103024116;