chr2-84653321-G-C

Position:

chr2-84653321-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001370.2(DNAH6):c.5081G>C(p.Gly1694Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.128 in 1,505,824 control chromosomes in the GnomAD database, including 12,907 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 986 hom., cov: 32)

Exomes 𝑓: 0.13 ( 11921 hom. )

Consequence

DNAH6
NM_001370.2 missense, splice_region

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 6.17

Variant links:

Genes affected

DNAH6 (HGNC:2951): (dynein axonemal heavy chain 6) This gene belongs to the dynein family, whose members encode large proteins that are constituents of the microtubule-associated motor protein complex. This complex is composed of dynein heavy, intermediate and light chains, which can be axonemal or cytoplasmic. This protein is an axonemal dynein heavy chain. It is involved in producing force for ciliary beating by using energy from ATP hydrolysis. Mutations in this gene may cause primary ciliary dyskinesia (PCD) as well as heterotaxy. [provided by RefSeq, Jun 2016]

DNAH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNAH6. . Gene score misZ 3.5535 (greater than the threshold 3.09). Trascript score misZ 3.4022 (greater than threshold 3.09). GenCC has associacion of gene with male infertility with azoospermia or oligozoospermia due to single gene mutation.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020864606).

BP6

Variant 2-84653321-G-C is Benign according to our data. Variant chr2-84653321-G-C is described in ClinVar as [Benign]. Clinvar id is 402738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH6	NM_001370.2 linkuse as main transcript	c.5081G>C	p.Gly1694Ala	missense_variant, splice_region_variant	34/77	ENST00000389394.8	NP_001361.1	Q9C0G6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8 linkuse as main transcript	c.5081G>C	p.Gly1694Ala	missense_variant, splice_region_variant	34/77	5	NM_001370.2	ENSP00000374045.3		Q9C0G6-1

Frequencies

GnomAD3 genomes

AF:

0.110

AC:

16774

AN:

151970

Hom.:

987

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0718

Gnomad AMI

AF:

0.116

Gnomad AMR

AF:

0.119

Gnomad ASJ

AF:

0.173

Gnomad EAS

AF:

0.0693

Gnomad SAS

AF:

0.130

Gnomad FIN

AF:

0.0802

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.133

GnomAD3 exomes

AF:

0.118

AC:

14938

AN:

127044

Hom.:

994

AF XY:

0.120

AC XY:

8013

AN XY:

66996

show subpopulations

Gnomad AFR exome

AF:

0.0672

Gnomad AMR exome

AF:

0.0959

Gnomad ASJ exome

AF:

0.182

Gnomad EAS exome

AF:

0.0617

Gnomad SAS exome

AF:

0.138

Gnomad FIN exome

AF:

0.0771

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.138

GnomAD4 exome

AF:

0.129

AC:

175272

AN:

1353736

Hom.:

11921

Cov.:

AF XY:

0.131

AC XY:

86900

AN XY:

663372

show subpopulations

Gnomad4 AFR exome

AF:

0.0710

Gnomad4 AMR exome

AF:

0.0953

Gnomad4 ASJ exome

AF:

0.180

Gnomad4 EAS exome

AF:

0.0698

Gnomad4 SAS exome

AF:

0.134

Gnomad4 FIN exome

AF:

0.0765

Gnomad4 NFE exome

AF:

0.134

Gnomad4 OTH exome

AF:

0.133

GnomAD4 genome

AF:

0.110

AC:

16775

AN:

152088

Hom.:

986

Cov.:

AF XY:

0.108

AC XY:

8055

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0717

Gnomad4 AMR

AF:

0.119

Gnomad4 ASJ

AF:

0.173

Gnomad4 EAS

AF:

0.0688

Gnomad4 SAS

AF:

0.131

Gnomad4 FIN

AF:

0.0802

Gnomad4 NFE

AF:

0.134

Gnomad4 OTH

AF:

0.133

Alfa

AF:

0.131

Hom.:

999

Bravo

AF:

0.109

TwinsUK

AF:

0.132

AC:

489

ALSPAC

AF:

0.127

AC:

490

ESP6500AA

AF:

0.0744

AC:

103

ESP6500EA

AF:

0.134

AC:

425

ExAC

AF:

0.111

AC:

2737

Asia WGS

AF:

0.0980

AC:

340

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

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 -

DNAH6-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as 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

0.19

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.068

T;T

Eigen

Benign

0.024

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

D;.

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.74

N;N

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.079

Sift

Benign

0.45

T;T

Polyphen

0.15

B;B

Vest4

0.28

MPC

0.11

ClinPred

0.017

GERP RS

5.0

Varity_R

0.32

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over