2-84670393-A-G

Variant names:

• chr2-84670393-A-G
• rs1881095
• NM_001370.2:c.6372A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001370.2(DNAH6):​c.6372A>G​(p.Leu2124Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.956 in 1,546,402 control chromosomes in the GnomAD database, including 706,541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71228 hom., cov: 33)
  • Exomes 𝑓: 0.95 (635313 hom.)
• Consequence: DNAH6 NM_001370.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0500
• Publications: 10 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-84670393-A-G is Benign according to our data. Variant chr2-84670393-A-G is described in ClinVar as Benign. ClinVar VariationId is 402740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.983 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.6372A>G	p.Leu2124Leu	synonymous_variant	Exon 39 of 77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.6372A>G	p.Leu2124Leu	synonymous_variant	Exon 39 of 77	5	NM_001370.2	ENSP00000374045.3
DNAH6	ENST00000602588.1	n.600A>G		non_coding_transcript_exon_variant	Exon 4 of 11	1

Frequencies

GnomAD3 genomes AF: 0.967 AC: 147147 AN: 152224 Hom.: 71168 Cov.: 33

Gnomad AFR AF: 0.991

Gnomad AMI AF: 0.916

Gnomad AMR AF: 0.967

Gnomad ASJ AF: 0.985

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.983

Gnomad FIN AF: 0.959

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.949

Gnomad OTH AF: 0.969

GnomAD2 exomes AF: 0.968 AC: 149284 AN: 154206 AF XY: 0.969

Gnomad AFR exome AF: 0.993

Gnomad AMR exome AF: 0.978

Gnomad ASJ exome AF: 0.988

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.962

Gnomad NFE exome AF: 0.949

Gnomad OTH exome AF: 0.964

GnomAD4 exome AF: 0.955 AC: 1330667 AN: 1394060 Hom.: 635313 Cov.: 33 AF XY: 0.955 AC XY: 656941 AN XY: 687598

African (AFR) AF: 0.993 AC: 31237 AN: 31462

American (AMR) AF: 0.978 AC: 34602 AN: 35372

Ashkenazi Jewish (ASJ) AF: 0.989 AC: 24829 AN: 25116

East Asian (EAS) AF: 1.00 AC: 35602 AN: 35604

South Asian (SAS) AF: 0.983 AC: 76820 AN: 78184

European-Finnish (FIN) AF: 0.962 AC: 47404 AN: 49268

Middle Eastern (MID) AF: 0.966 AC: 5488 AN: 5680

European-Non Finnish (NFE) AF: 0.948 AC: 1019197 AN: 1075522

Other (OTH) AF: 0.959 AC: 55488 AN: 57852

GnomAD4 genome AF: 0.967 AC: 147266 AN: 152342 Hom.: 71228 Cov.: 33 AF XY: 0.968 AC XY: 72082 AN XY: 74496

African (AFR) AF: 0.991 AC: 41204 AN: 41580

American (AMR) AF: 0.967 AC: 14795 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.985 AC: 3420 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5182 AN: 5182

South Asian (SAS) AF: 0.983 AC: 4748 AN: 4830

European-Finnish (FIN) AF: 0.959 AC: 10190 AN: 10622

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.949 AC: 64559 AN: 68040

Other (OTH) AF: 0.970 AC: 2048 AN: 2112

Alfa AF: 0.959 Hom.: 137192

Bravo AF: 0.969

Asia WGS AF: 0.990 AC: 3439 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

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: MAF

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.8
DANN	Benign	0.77
PhyloP100		-0.050
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1881095; hg19: chr2-84897517; COSMIC: COSV108041477;