2-84797607-C-T

Variant names:

• chr2-84797607-C-T
• rs1192395
• NM_001370.2:c.11430C>T

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.11430C>T​(p.Ile3810Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,550,648 control chromosomes in the GnomAD database, including 12,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1160 hom., cov: 32)
  • Exomes 𝑓: 0.13 (11474 hom.)
• Consequence: DNAH6 NM_001370.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.58

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=-0.27).
• BP6: Variant 2-84797607-C-T is Benign according to our data. Variant chr2-84797607-C-T is described in ClinVar as [Benign]. Clinvar id is 402746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.11430C>T	p.Ile3810Ile	synonymous_variant	Exon 70 of 77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.11430C>T	p.Ile3810Ile	synonymous_variant	Exon 70 of 77	5	NM_001370.2	ENSP00000374045.3

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18632 AN: 152050 Hom.: 1159 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0786

Gnomad SAS AF: 0.0877

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.124 AC: 19401 AN: 157092 Hom.: 1336 AF XY: 0.121 AC XY: 10042 AN XY: 83076

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.0772

Gnomad SAS exome AF: 0.0944

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.125 AC: 174910 AN: 1398480 Hom.: 11474 Cov.: 31 AF XY: 0.124 AC XY: 85741 AN XY: 689776

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.153

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.0722

Gnomad4 SAS exome AF: 0.0939

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.122 AC: 18640 AN: 152168 Hom.: 1160 Cov.: 32 AF XY: 0.121 AC XY: 9020 AN XY: 74398

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.0780

Gnomad4 SAS AF: 0.0871

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.132

Alfa AF: 0.120 Hom.: 1620

Bravo AF: 0.122

Asia WGS AF: 0.0980 AC: 341 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: 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	-0.27
CADD	Benign	8.5
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: rs1192395; hg19: chr2-85024731; COSMIC: COSV52861533;