Genetic Variant DNAH6:p.Arg3292Cys (chr2-84722706-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001370.2(DNAH6):c.9874C>T(p.Arg3292Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,548,330 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

DNAH6
NM_001370.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.28

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2 link	c.9874C>T	p.Arg3292Cys	missense_variant	Exon 60 of 77	ENST00000389394.8	NP_001361.1	Q9C0G6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8 link	c.9874C>T	p.Arg3292Cys	missense_variant	Exon 60 of 77	5	NM_001370.2	ENSP00000374045.3		Q9C0G6-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000235

AC:

AN:

153518

Hom.:

AF XY:

0.000233

AC XY:

AN XY:

81384

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000762

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000316

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000231

AC:

322

AN:

1396150

Hom.:

Cov.:

AF XY:

0.000241

AC XY:

166

AN XY:

688728

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000686

Gnomad4 FIN exome

AF:

0.0000406

Gnomad4 NFE exome

AF:

0.000221

Gnomad4 OTH exome

AF:

0.000363

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000245

Hom.:

Bravo

AF:

0.000185

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000318

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Sep 29, 2017

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spermatogenic Failure

Uncertain:1

Nov 28, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

0.97

D;.

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.66

D;D

MetaSVM

Uncertain

0.0085

MutationAssessor

Pathogenic

3.5

H;H

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.68

MVP

0.63

MPC

0.52

ClinPred

0.52

GERP RS

4.8

Varity_R

0.39

gMVP

0.68

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