2-84653321-G-C

Variant names:

• chr2-84653321-G-C
• rs28375417
• NM_001370.2:c.5081G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 12/21 in silico tools predict 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.17
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 rank	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.5081G>C	p.Gly1694Ala	missense_variant, splice_region_variant	Exon 34 of 77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.5081G>C	p.Gly1694Ala	missense_variant, splice_region_variant	Exon 34 of 77	5	NM_001370.2	ENSP00000374045.3

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16774 AN: 151970 Hom.: 987 Cov.: 32

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

GnomAD2 exomes AF: 0.118 AC: 14938 AN: 127044 AF XY: 0.120

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 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.: 31 AF XY: 0.131 AC XY: 86900 AN XY: 663372

African (AFR) AF: 0.0710 AC: 2095 AN: 29526

American (AMR) AF: 0.0953 AC: 2593 AN: 27216

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4086 AN: 22734

East Asian (EAS) AF: 0.0698 AC: 2458 AN: 35238

South Asian (SAS) AF: 0.134 AC: 9775 AN: 72872

European-Finnish (FIN) AF: 0.0765 AC: 3660 AN: 47850

Middle Eastern (MID) AF: 0.203 AC: 1105 AN: 5446

European-Non Finnish (NFE) AF: 0.134 AC: 142066 AN: 1056944

Other (OTH) AF: 0.133 AC: 7434 AN: 55910

GnomAD4 genome AF: 0.110 AC: 16775 AN: 152088 Hom.: 986 Cov.: 32 AF XY: 0.108 AC XY: 8055 AN XY: 74350

African (AFR) AF: 0.0717 AC: 2975 AN: 41508

American (AMR) AF: 0.119 AC: 1813 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 599 AN: 3466

East Asian (EAS) AF: 0.0688 AC: 357 AN: 5186

South Asian (SAS) AF: 0.131 AC: 629 AN: 4816

European-Finnish (FIN) AF: 0.0802 AC: 849 AN: 10582

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9103 AN: 67960

Other (OTH) AF: 0.133 AC: 281 AN: 2112

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

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Benign	0.84
DEOGEN2	Benign	0.068	T;T
Eigen	Benign	0.024
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;.
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.74	N;N
PhyloP100		6.2
PrimateAI	Uncertain	0.76	T
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	T
GERP RS		5.0
Varity_R		0.32
gMVP		0.63
Mutation Taster		=41/59	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28375417; hg19: chr2-84880445; COSMIC: COSV52862202; COSMIC: COSV52862202;