rs78190897

Positions:

chr2-84697699-T-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.7649T>C(p.Val2550Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,551,366 control chromosomes in the GnomAD database, including 19,734 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1696 hom., cov: 32)

Exomes 𝑓: 0.16 ( 18038 hom. )

Consequence

DNAH6
NM_001370.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.63

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=5.598068E-4).

BP6

Variant 2-84697699-T-C is Benign according to our data. Variant chr2-84697699-T-C is described in ClinVar as [Benign]. Clinvar id is 402742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH6	NM_001370.2 linkuse as main transcript	c.7649T>C	p.Val2550Ala	missense_variant	47/77	ENST00000389394.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH6	ENST00000389394.8 linkuse as main transcript	c.7649T>C	p.Val2550Ala	missense_variant	47/77	5	NM_001370.2	P1	Q9C0G6-1
DNAH6	ENST00000602588.1 linkuse as main transcript	n.1730T>C		non_coding_transcript_exon_variant	11/11	1

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

22043

AN:

151878

Hom.:

1697

Cov.:

show subpopulations

Gnomad AFR

AF:

0.118

Gnomad AMI

AF:

0.326

Gnomad AMR

AF:

0.139

Gnomad ASJ

AF:

0.239

Gnomad EAS

AF:

0.0798

Gnomad SAS

AF:

0.109

Gnomad FIN

AF:

0.147

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.162

Gnomad OTH

AF:

0.163

GnomAD3 exomes

AF:

0.152

AC:

24009

AN:

157456

Hom.:

1990

AF XY:

0.152

AC XY:

12623

AN XY:

83230

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.168

Gnomad ASJ exome

AF:

0.245

Gnomad EAS exome

AF:

0.0796

Gnomad SAS exome

AF:

0.121

Gnomad FIN exome

AF:

0.143

Gnomad NFE exome

AF:

0.164

Gnomad OTH exome

AF:

0.167

GnomAD4 exome

AF:

0.158

AC:

220616

AN:

1399370

Hom.:

18038

Cov.:

AF XY:

0.157

AC XY:

108449

AN XY:

690220

show subpopulations

Gnomad4 AFR exome

AF:

0.114

Gnomad4 AMR exome

AF:

0.167

Gnomad4 ASJ exome

AF:

0.248

Gnomad4 EAS exome

AF:

0.0718

Gnomad4 SAS exome

AF:

0.123

Gnomad4 FIN exome

AF:

0.148

Gnomad4 NFE exome

AF:

0.162

Gnomad4 OTH exome

AF:

0.155

GnomAD4 genome

AF:

0.145

AC:

22045

AN:

151996

Hom.:

1696

Cov.:

AF XY:

0.143

AC XY:

10611

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.118

Gnomad4 AMR

AF:

0.139

Gnomad4 ASJ

AF:

0.239

Gnomad4 EAS

AF:

0.0792

Gnomad4 SAS

AF:

0.108

Gnomad4 FIN

AF:

0.147

Gnomad4 NFE

AF:

0.162

Gnomad4 OTH

AF:

0.163

Alfa

AF:

0.161

Hom.:

3096

Bravo

AF:

0.145

TwinsUK

AF:

0.149

AC:

554

ALSPAC

AF:

0.171

AC:

660

ESP6500AA

AF:

0.126

AC:

175

ESP6500EA

AF:

0.166

AC:

528

ExAC

AF:

0.136

AC:

3458

Asia WGS

AF:

0.106

AC:

369

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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, criteria provided, single submitter

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). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.0030

DANN

Benign

0.54

DEOGEN2

Benign

0.00050

T;T

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0091

LIST_S2

Benign

0.61

T;.

MetaRNN

Benign

0.00056

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-2.3

N;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.35

PROVEAN

Benign

1.5

N;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.028

MPC

0.098

ClinPred

0.0070

GERP RS

-11

Varity_R

0.060

gMVP

0.29

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

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