rs1192295

Positions:

• chr2-84694309-A-G

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.7353A>G​(p.Thr2451Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0621 in 1,552,234 control chromosomes in the GnomAD database, including 4,495 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1343 hom., cov: 33)
  • Exomes 𝑓: 0.058 (3152 hom.)
• Consequence: DNAH6 NM_001370.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.139

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-84694309-A-G is Benign according to our data. Variant chr2-84694309-A-G is described in ClinVar as [Benign]. Clinvar id is 402741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.139 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.7353A>G	p.Thr2451Thr	synonymous_variant	46/77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.7353A>G	p.Thr2451Thr	synonymous_variant	46/77	5	NM_001370.2	ENSP00000374045.3
DNAH6	ENST00000602588.1	n.1434A>G		non_coding_transcript_exon_variant	10/11	1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15521 AN: 152206 Hom.: 1342 Cov.: 33

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0593

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00211

Gnomad SAS AF: 0.0610

Gnomad FIN AF: 0.0409

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0556

Gnomad OTH AF: 0.0812

GnomAD3 exomes AF: 0.0553 AC: 8768 AN: 158578 Hom.: 429 AF XY: 0.0530 AC XY: 4430 AN XY: 83574

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.0343

Gnomad ASJ exome AF: 0.0198

Gnomad EAS exome AF: 0.00128

Gnomad SAS exome AF: 0.0649

Gnomad FIN exome AF: 0.0381

Gnomad NFE exome AF: 0.0546

Gnomad OTH exome AF: 0.0515

GnomAD4 exome AF: 0.0578 AC: 80911 AN: 1399910 Hom.: 3152 Cov.: 31 AF XY: 0.0573 AC XY: 39574 AN XY: 690446

Gnomad4 AFR exome AF: 0.239

Gnomad4 AMR exome AF: 0.0376

Gnomad4 ASJ exome AF: 0.0192

Gnomad4 EAS exome AF: 0.000811

Gnomad4 SAS exome AF: 0.0644

Gnomad4 FIN exome AF: 0.0386

Gnomad4 NFE exome AF: 0.0560

Gnomad4 OTH exome AF: 0.0637

GnomAD4 genome AF: 0.102 AC: 15544 AN: 152324 Hom.: 1343 Cov.: 33 AF XY: 0.0994 AC XY: 7401 AN XY: 74494

Gnomad4 AFR AF: 0.235

Gnomad4 AMR AF: 0.0592

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0613

Gnomad4 FIN AF: 0.0409

Gnomad4 NFE AF: 0.0556

Gnomad4 OTH AF: 0.0803

Alfa AF: 0.0604 Hom.: 963

Bravo AF: 0.107

Asia WGS AF: 0.0460 AC: 162 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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: MAF -

DNAH6-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

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	-0.61
CADD	Benign	3.1
DANN	Benign	0.66

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: rs1192295; hg19: chr2-84921433;