2-195875800-T-C

Variant names:

• chr2-195875800-T-C
• rs62623377
• NM_018897.3:c.6161A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_018897.3(DNAH7):​c.6161A>G​(p.Tyr2054Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0226 in 1,613,136 control chromosomes in the GnomAD database, including 493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (32 hom., cov: 32)
  • Exomes 𝑓: 0.023 (461 hom.)
• Consequence: DNAH7 NM_018897.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.07
• Publications: 9 publications found

Genes affected

DNAH7 (HGNC:18661): (dynein axonemal heavy chain 7) DNAH7 is a component of the inner dynein arm of ciliary axonemes (Zhang et al., 2002 [PubMed 11877439]).[supplied by OMIM, Mar 2008]

DNAH7 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 50

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• male infertility with azoospermia or oligozoospermia due to single gene mutation

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

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 2-195875800-T-C is Benign according to our data. Variant chr2-195875800-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 402758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0163 (2478/152252) while in subpopulation NFE AF = 0.0247 (1679/67978). AF 95% confidence interval is 0.0237. There are 32 homozygotes in GnomAd4. There are 1154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH7	NM_018897.3	c.6161A>G	p.Tyr2054Cys	missense_variant	Exon 38 of 65	ENST00000312428.11	NP_061720.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH7	ENST00000312428.11	c.6161A>G	p.Tyr2054Cys	missense_variant	Exon 38 of 65	1	NM_018897.3	ENSP00000311273.6

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2477 AN: 152134 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0177 AC: 4382 AN: 248262 AF XY: 0.0184

Gnomad AFR exome AF: 0.00317

Gnomad AMR exome AF: 0.00719

Gnomad ASJ exome AF: 0.0198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0225

Gnomad NFE exome AF: 0.0246

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.0233 AC: 33967 AN: 1460884 Hom.: 461 Cov.: 31 AF XY: 0.0230 AC XY: 16746 AN XY: 726710

African (AFR) AF: 0.00347 AC: 116 AN: 33432

American (AMR) AF: 0.00787 AC: 350 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 505 AN: 26102

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39684

South Asian (SAS) AF: 0.0171 AC: 1468 AN: 85988

European-Finnish (FIN) AF: 0.0258 AC: 1377 AN: 53406

Middle Eastern (MID) AF: 0.00573 AC: 33 AN: 5764

European-Non Finnish (NFE) AF: 0.0260 AC: 28849 AN: 1111666

Other (OTH) AF: 0.0210 AC: 1266 AN: 60354

GnomAD4 genome AF: 0.0163 AC: 2478 AN: 152252 Hom.: 32 Cov.: 32 AF XY: 0.0155 AC XY: 1154 AN XY: 74454

African (AFR) AF: 0.00423 AC: 176 AN: 41568

American (AMR) AF: 0.0117 AC: 179 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4826

European-Finnish (FIN) AF: 0.0245 AC: 260 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0247 AC: 1679 AN: 67978

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0218 Hom.: 142

Bravo AF: 0.0149

TwinsUK AF: 0.0248 AC: 92

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.00347 AC: 13

ESP6500EA AF: 0.0246 AC: 202

ExAC AF: 0.0183 AC: 2209

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0241

EpiControl AF: 0.0232

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely 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: Axonemal dynein/candidate PCD gene, but frequency of this variant is high -

DNAH7-related disorder Benign:1

Jun 18, 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). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.019	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.6	D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.37
MPC		0.25
ClinPred		0.065	T
GERP RS		5.0
Varity_R		0.87
gMVP		0.83
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.57		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs62623377; hg19: chr2-196740524; COSMIC: COSV56752438;