NM_001370.2:c.1818C>A

Variant names:

• chr2-84573481-C-A
• rs11891970
• NM_001370.2:c.1818C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001370.2(DNAH6):​c.1818C>A​(p.Ala606Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.944 in 1,577,730 control chromosomes in the GnomAD database, including 703,947 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (64798 hom., cov: 33)
  • Exomes 𝑓: 0.95 (639149 hom.)
• Consequence: DNAH6 NM_001370.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.364
• Publications: 11 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-84573481-C-A is Benign according to our data. Variant chr2-84573481-C-A is described in ClinVar as Benign. ClinVar VariationId is 402734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.364 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.1818C>A	p.Ala606Ala	synonymous_variant	Exon 12 of 77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.1818C>A	p.Ala606Ala	synonymous_variant	Exon 12 of 77	5	NM_001370.2	ENSP00000374045.3
DNAH6	ENST00000494025.1	n.861C>A		non_coding_transcript_exon_variant	Exon 6 of 9	1
DNAH6	ENST00000476689.5	n.1168C>A		non_coding_transcript_exon_variant	Exon 8 of 11	2

Frequencies

GnomAD3 genomes AF: 0.921 AC: 140152 AN: 152160 Hom.: 64767 Cov.: 33

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.916

Gnomad AMR AF: 0.950

Gnomad ASJ AF: 0.984

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.950

Gnomad FIN AF: 0.959

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.947

Gnomad OTH AF: 0.936

GnomAD2 exomes AF: 0.949 AC: 206970 AN: 218172 AF XY: 0.951

Gnomad AFR exome AF: 0.830

Gnomad AMR exome AF: 0.969

Gnomad ASJ exome AF: 0.985

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.963

Gnomad NFE exome AF: 0.947

Gnomad OTH exome AF: 0.952

GnomAD4 exome AF: 0.947 AC: 1349390 AN: 1425452 Hom.: 639149 Cov.: 35 AF XY: 0.947 AC XY: 671555 AN XY: 708898

African (AFR) AF: 0.830 AC: 25722 AN: 31008

American (AMR) AF: 0.967 AC: 32962 AN: 34072

Ashkenazi Jewish (ASJ) AF: 0.985 AC: 24710 AN: 25078

East Asian (EAS) AF: 0.999 AC: 38077 AN: 38116

South Asian (SAS) AF: 0.952 AC: 75051 AN: 78820

European-Finnish (FIN) AF: 0.962 AC: 51121 AN: 53140

Middle Eastern (MID) AF: 0.953 AC: 5411 AN: 5676

European-Non Finnish (NFE) AF: 0.946 AC: 1040674 AN: 1100602

Other (OTH) AF: 0.944 AC: 55662 AN: 58940

GnomAD4 genome AF: 0.921 AC: 140239 AN: 152278 Hom.: 64798 Cov.: 33 AF XY: 0.923 AC XY: 68701 AN XY: 74456

African (AFR) AF: 0.839 AC: 34860 AN: 41530

American (AMR) AF: 0.950 AC: 14540 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.984 AC: 3412 AN: 3468

East Asian (EAS) AF: 0.997 AC: 5168 AN: 5182

South Asian (SAS) AF: 0.950 AC: 4581 AN: 4824

European-Finnish (FIN) AF: 0.959 AC: 10191 AN: 10626

Middle Eastern (MID) AF: 0.946 AC: 278 AN: 294

European-Non Finnish (NFE) AF: 0.947 AC: 64393 AN: 68030

Other (OTH) AF: 0.937 AC: 1981 AN: 2114

Alfa AF: 0.941 Hom.: 99443

Bravo AF: 0.918

Asia WGS AF: 0.966 AC: 3361 AN: 3478

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: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	3.9
DANN	Benign	0.36
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs11891970; hg19: chr2-84800605; COSMIC: COSV108041475;