2-84544443-C-T

Variant names:

• chr2-84544443-C-T
• rs1542477
• NM_001370.2:c.873C>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.873C>T​(p.Ser291Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 1,528,912 control chromosomes in the GnomAD database, including 640,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (53456 hom., cov: 32)
  • Exomes 𝑓: 0.92 (587436 hom.)
• Consequence: DNAH6 NM_001370.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.457

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=-0.38).
• BP6: Variant 2-84544443-C-T is Benign according to our data. Variant chr2-84544443-C-T is described in ClinVar as [Benign]. Clinvar id is 402733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.457 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.873C>T	p.Ser291Ser	synonymous_variant	Exon 5 of 77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.873C>T	p.Ser291Ser	synonymous_variant	Exon 5 of 77	5	NM_001370.2	ENSP00000374045.3
DNAH6	ENST00000494025.1	n.230-3845C>T		intron_variant	Intron 1 of 8	1
DNAH6	ENST00000476689.5	n.537-3845C>T		intron_variant	Intron 3 of 10	2
DNAH6	ENST00000468661.1	n.*114C>T		downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.818 AC: 124372 AN: 151980 Hom.: 53448 Cov.: 32

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.902

Gnomad AMR AF: 0.890

Gnomad ASJ AF: 0.936

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.890

Gnomad FIN AF: 0.955

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.933

Gnomad OTH AF: 0.847

GnomAD3 exomes AF: 0.911 AC: 140725 AN: 154432 Hom.: 64835 AF XY: 0.914 AC XY: 74884 AN XY: 81936

Gnomad AFR exome AF: 0.509

Gnomad AMR exome AF: 0.937

Gnomad ASJ exome AF: 0.932

Gnomad EAS exome AF: 0.989

Gnomad SAS exome AF: 0.889

Gnomad FIN exome AF: 0.957

Gnomad NFE exome AF: 0.932

Gnomad OTH exome AF: 0.920

GnomAD4 exome AF: 0.921 AC: 1268318 AN: 1376814 Hom.: 587436 Cov.: 32 AF XY: 0.921 AC XY: 626734 AN XY: 680216

Gnomad4 AFR exome AF: 0.510

Gnomad4 AMR exome AF: 0.931

Gnomad4 ASJ exome AF: 0.934

Gnomad4 EAS exome AF: 0.978

Gnomad4 SAS exome AF: 0.890

Gnomad4 FIN exome AF: 0.957

Gnomad4 NFE exome AF: 0.933

Gnomad4 OTH exome AF: 0.900

GnomAD4 genome AF: 0.818 AC: 124418 AN: 152098 Hom.: 53456 Cov.: 32 AF XY: 0.822 AC XY: 61129 AN XY: 74338

Gnomad4 AFR AF: 0.526

Gnomad4 AMR AF: 0.891

Gnomad4 ASJ AF: 0.936

Gnomad4 EAS AF: 0.986

Gnomad4 SAS AF: 0.890

Gnomad4 FIN AF: 0.955

Gnomad4 NFE AF: 0.933

Gnomad4 OTH AF: 0.848

Alfa AF: 0.877 Hom.: 27044

Bravo AF: 0.803

Asia WGS AF: 0.908 AC: 3150 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Nov 01, 2018

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	10
DANN	Benign	0.74

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: rs1542477; hg19: chr2-84771567;