rs78190897

Variant names:

• chr2-84697699-T-C
• rs78190897
• NM_001370.2:c.7649T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-84697699-T-C
• chr2-84697699-T-G

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.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. 15/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.63
• 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=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 VariationId 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 rank	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.7649T>C	p.Val2550Ala	missense_variant	Exon 47 of 77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.7649T>C	p.Val2550Ala	missense_variant	Exon 47 of 77	5	NM_001370.2	ENSP00000374045.3
DNAH6	ENST00000602588.1	n.1730T>C		non_coding_transcript_exon_variant	Exon 11 of 11	1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22043 AN: 151878 Hom.: 1697 Cov.: 32

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

GnomAD2 exomes AF: 0.152 AC: 24009 AN: 157456 AF XY: 0.152

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 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.: 32 AF XY: 0.157 AC XY: 108449 AN XY: 690220

African (AFR) AF: 0.114 AC: 3615 AN: 31596

American (AMR) AF: 0.167 AC: 5967 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 6242 AN: 25178

East Asian (EAS) AF: 0.0718 AC: 2566 AN: 35728

South Asian (SAS) AF: 0.123 AC: 9711 AN: 79232

European-Finnish (FIN) AF: 0.148 AC: 7321 AN: 49348

Middle Eastern (MID) AF: 0.171 AC: 973 AN: 5700

European-Non Finnish (NFE) AF: 0.162 AC: 175229 AN: 1078824

Other (OTH) AF: 0.155 AC: 8992 AN: 58062

GnomAD4 genome AF: 0.145 AC: 22045 AN: 151996 Hom.: 1696 Cov.: 32 AF XY: 0.143 AC XY: 10611 AN XY: 74304

African (AFR) AF: 0.118 AC: 4887 AN: 41460

American (AMR) AF: 0.139 AC: 2120 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 829 AN: 3470

East Asian (EAS) AF: 0.0792 AC: 410 AN: 5176

South Asian (SAS) AF: 0.108 AC: 521 AN: 4802

European-Finnish (FIN) AF: 0.147 AC: 1557 AN: 10562

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11038 AN: 67960

Other (OTH) AF: 0.163 AC: 343 AN: 2110

Alfa AF: 0.158 Hom.: 4157

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: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	0.047
BayesDel_addAF	Benign	-0.85	T
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	N
LIST_S2	Benign	0.61	T;.
MetaRNN	Benign	0.00056	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-2.3	N;N
PhyloP100		-1.6
PrimateAI	Benign	0.35	T
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	T
GERP RS		-11
Varity_R		0.060
gMVP		0.29
Mutation Taster		=86/14	polymorphism (auto)

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

Other links and lift over

dbSNP: rs78190897; hg19: chr2-84924823; COSMIC: COSV52861513;