rs61737514

Positions:

• chr11-103323958-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000375735.7(DYNC2H1):​c.12007G>A​(p.Ala4003Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,611,986 control chromosomes in the GnomAD database, including 16 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 0.0056 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (10 hom.)
• Consequence: DYNC2H1 ENST00000375735.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 9.17

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008333504).
• BP6: Variant 11-103323958-G-A is Benign according to our data. Variant chr11-103323958-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215482.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00559 (849/151990) while in subpopulation AFR AF= 0.019 (788/41426). AF 95% confidence interval is 0.0179. There are 6 homozygotes in gnomad4. There are 414 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.12028G>A	p.Ala4010Thr	missense_variant	83/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.12007G>A	p.Ala4003Thr	missense_variant	82/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.12028G>A	p.Ala4010Thr	missense_variant	83/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.12007G>A	p.Ala4003Thr	missense_variant	82/89	1	NM_001377.3	ENSP00000364887	P3
DYNC2H1	ENST00000334267.11	c.2206-111985G>A		intron_variant		1		ENSP00000334021
DYNC2H1	ENST00000528670.5	c.*53G>A		3_prime_UTR_variant, NMD_transcript_variant	10/17	5		ENSP00000433451

Frequencies

GnomAD3 genomes AF: 0.00557 AC: 846 AN: 151872 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00528

GnomAD3 exomes AF: 0.00149 AC: 371 AN: 248632 Hom.: 5 AF XY: 0.00110 AC XY: 148 AN XY: 134884

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000623 AC: 909 AN: 1459996 Hom.: 10 Cov.: 30 AF XY: 0.000548 AC XY: 398 AN XY: 726226

Gnomad4 AFR exome AF: 0.0189

Gnomad4 AMR exome AF: 0.000873

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000939

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00559 AC: 849 AN: 151990 Hom.: 6 Cov.: 32 AF XY: 0.00557 AC XY: 414 AN XY: 74290

Gnomad4 AFR AF: 0.0190

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00115 Hom.: 4

Bravo AF: 0.00670

ESP6500AA AF: 0.0195 AC: 73

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.00194 AC: 234

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -
Benign, 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 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. -

Short rib-polydactyly syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 29, 2017

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:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T;T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;.;D
MetaRNN	Benign	0.0083	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.42	N;.;.;N
REVEL	Benign	0.22
Sift	Benign	0.058	T;.;.;T
Sift4G	Benign	0.076	T;.;.;T
Polyphen		0.067	B;B;P;P
Vest4		0.54
MVP		0.58
MPC		0.066
ClinPred		0.039	T
GERP RS		5.8
Varity_R		0.17
gMVP		0.36

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: rs61737514; hg19: chr11-103194686;