rs754273

Variant names:

• chr2-84796430-A-G
• rs754273
• NM_001370.2:c.11359+5A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001370.2(DNAH6):​c.11359+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,498,844 control chromosomes in the GnomAD database, including 23,880 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4611 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19269 hom.)
• Consequence: DNAH6 NM_001370.2 splice_region, intron
• Scores: Splicing: ADA: 0.0002191
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.310

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-84796430-A-G is Benign according to our data. Variant chr2-84796430-A-G is described in ClinVar as [Benign]. Clinvar id is 402745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.11359+5A>G		splice_region_variant, intron_variant	Intron 69 of 76	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.11359+5A>G		splice_region_variant, intron_variant	Intron 69 of 76	5	NM_001370.2	ENSP00000374045.3

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34190 AN: 151944 Hom.: 4587 Cov.: 32

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.224

GnomAD3 exomes AF: 0.174 AC: 22643 AN: 130108 Hom.: 2279 AF XY: 0.169 AC XY: 11648 AN XY: 68916

Gnomad AFR exome AF: 0.402

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.102

Gnomad SAS exome AF: 0.152

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.162 AC: 218027 AN: 1346782 Hom.: 19269 Cov.: 26 AF XY: 0.162 AC XY: 107328 AN XY: 662922

Gnomad4 AFR exome AF: 0.404

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.128

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.172

GnomAD4 genome AF: 0.225 AC: 34259 AN: 152062 Hom.: 4611 Cov.: 32 AF XY: 0.222 AC XY: 16545 AN XY: 74362

Gnomad4 AFR AF: 0.395

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.176

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.224

Alfa AF: 0.172 Hom.: 2854

Bravo AF: 0.236

Asia WGS AF: 0.155 AC: 541 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 -

DNAH6-related disorder Benign:1

Oct 28, 2019

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	-0.79
CADD	Benign	8.3
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.062
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: rs754273; hg19: chr2-85023554; COSMIC: COSV52875853;