rs1037863

Positions:

• chr2-84544356-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001370.2(DNAH6):​c.786G>A​(p.Leu262=) 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 1,544,810 control chromosomes in the GnomAD database, including 689,075 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (64732 hom., cov: 31)
  • Exomes 𝑓: 0.95 (624343 hom.)
• Consequence: DNAH6 NM_001370.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.61

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-84544356-G-A is Benign according to our data. Variant chr2-84544356-G-A is described in ClinVar as [Benign]. Clinvar id is 402732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.61 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/exons	MANE	UniProt
DNAH6	NM_001370.2	c.786G>A	p.Leu262=	synonymous_variant	5/77	ENST00000389394.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH6	ENST00000389394.8	c.786G>A	p.Leu262=	synonymous_variant	5/77	5	NM_001370.2	P1
DNAH6	ENST00000494025.1	n.230-3932G>A		intron_variant, non_coding_transcript_variant		1
DNAH6	ENST00000476689.5	n.537-3932G>A		intron_variant, non_coding_transcript_variant		2
DNAH6	ENST00000468661.1			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.921 AC: 140005 AN: 151998 Hom.: 64701 Cov.: 31

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

GnomAD3 exomes AF: 0.953 AC: 148898 AN: 156226 Hom.: 71046 AF XY: 0.955 AC XY: 79059 AN XY: 82776

Gnomad AFR exome AF: 0.834

Gnomad AMR exome AF: 0.970

Gnomad ASJ exome AF: 0.985

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.951

Gnomad FIN exome AF: 0.962

Gnomad NFE exome AF: 0.947

Gnomad OTH exome AF: 0.958

GnomAD4 exome AF: 0.947 AC: 1318246 AN: 1392694 Hom.: 624343 Cov.: 38 AF XY: 0.947 AC XY: 651145 AN XY: 687366

Gnomad4 AFR exome AF: 0.832

Gnomad4 AMR exome AF: 0.969

Gnomad4 ASJ exome AF: 0.985

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.952

Gnomad4 FIN exome AF: 0.962

Gnomad4 NFE exome AF: 0.945

Gnomad4 OTH exome AF: 0.944

GnomAD4 genome AF: 0.921 AC: 140092 AN: 152116 Hom.: 64732 Cov.: 31 AF XY: 0.923 AC XY: 68617 AN XY: 74360

Gnomad4 AFR AF: 0.839

Gnomad4 AMR AF: 0.951

Gnomad4 ASJ AF: 0.984

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.950

Gnomad4 FIN AF: 0.959

Gnomad4 NFE AF: 0.947

Gnomad4 OTH AF: 0.937

Alfa AF: 0.939 Hom.: 35535

Bravo AF: 0.918

Asia WGS AF: 0.966 AC: 3350 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.13
DANN	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs1037863; hg19: chr2-84771480;