rs1192344

Variant names:

• chr2-84718345-G-A
• rs1192344
• NM_001370.2:c.9753G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001370.2(DNAH6):​c.9753G>A​(p.Leu3251Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0563 in 1,545,136 control chromosomes in the GnomAD database, including 2,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (522 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2430 hom.)
• Consequence: DNAH6 NM_001370.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.510

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-84718345-G-A is Benign according to our data. Variant chr2-84718345-G-A is described in ClinVar as [Benign]. Clinvar id is 402744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.9753G>A	p.Leu3251Leu	synonymous_variant	Exon 59 of 77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.9753G>A	p.Leu3251Leu	synonymous_variant	Exon 59 of 77	5	NM_001370.2	ENSP00000374045.3

Frequencies

GnomAD3 genomes AF: 0.0711 AC: 10817 AN: 152094 Hom.: 517 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0474

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00211

Gnomad SAS AF: 0.0612

Gnomad FIN AF: 0.0407

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0552

Gnomad OTH AF: 0.0608

GnomAD3 exomes AF: 0.0491 AC: 7365 AN: 149880 Hom.: 246 AF XY: 0.0491 AC XY: 3887 AN XY: 79184

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.0306

Gnomad ASJ exome AF: 0.0204

Gnomad EAS exome AF: 0.00124

Gnomad SAS exome AF: 0.0669

Gnomad FIN exome AF: 0.0384

Gnomad NFE exome AF: 0.0547

Gnomad OTH exome AF: 0.0505

GnomAD4 exome AF: 0.0546 AC: 76112 AN: 1392924 Hom.: 2430 Cov.: 31 AF XY: 0.0546 AC XY: 37527 AN XY: 686726

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.0329

Gnomad4 ASJ exome AF: 0.0194

Gnomad4 EAS exome AF: 0.000814

Gnomad4 SAS exome AF: 0.0644

Gnomad4 FIN exome AF: 0.0386

Gnomad4 NFE exome AF: 0.0557

Gnomad4 OTH exome AF: 0.0573

GnomAD4 genome AF: 0.0712 AC: 10839 AN: 152212 Hom.: 522 Cov.: 32 AF XY: 0.0701 AC XY: 5214 AN XY: 74420

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.0473

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0615

Gnomad4 FIN AF: 0.0407

Gnomad4 NFE AF: 0.0552

Gnomad4 OTH AF: 0.0602

Alfa AF: 0.0582 Hom.: 211

Bravo AF: 0.0715

Asia WGS AF: 0.0410 AC: 143 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: MAF -

DNAH6-related disorder Benign:1

Jan 03, 2020

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
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.0
DANN	Benign	0.84

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: rs1192344; hg19: chr2-84945469;