2-84528925-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001370.2(DNAH6):c.421G>A(p.Val141Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.946 in 1,549,342 control chromosomes in the GnomAD database, including 694,396 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (65940 hom., cov: 25)
  • Exomes 𝑓: 0.95 (628456 hom.)
• Consequence: DNAH6 NM_001370.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.34

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.

• PP2: Missense variant where missense usually causes diseases, DNAH6
• BP4: Computational evidence support a benign effect (MetaRNN=9.98577E-7).
• BP6: Variant 2-84528925-G-A is Benign according to our data. Variant chr2-84528925-G-A is described in ClinVar as [Benign]. Clinvar id is 402731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH6	NM_001370.2	c.421G>A	p.Val141Met	missense_variant	4/77	ENST00000389394.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH6	ENST00000389394.8	c.421G>A	p.Val141Met	missense_variant	4/77	5	NM_001370.2	P1
DNAH6	ENST00000494025.1	n.229+10874G>A		intron_variant, non_coding_transcript_variant		1
DNAH6	ENST00000468661.1	n.454+3187G>A		intron_variant, non_coding_transcript_variant		4
DNAH6	ENST00000476689.5	n.536+3187G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.933 AC: 140971 AN: 151042 Hom.: 65906 Cov.: 25

Gnomad AFR AF: 0.882

Gnomad AMI AF: 0.916

Gnomad AMR AF: 0.954

Gnomad ASJ AF: 0.985

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.950

Gnomad FIN AF: 0.960

Gnomad MID AF: 0.956

Gnomad NFE AF: 0.947

Gnomad OTH AF: 0.946

GnomAD3 exomes AF: 0.956 AC: 149258 AN: 156142 Hom.: 71392 AF XY: 0.957 AC XY: 79215 AN XY: 82756

Gnomad AFR exome AF: 0.880

Gnomad AMR exome AF: 0.972

Gnomad ASJ exome AF: 0.985

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.951

Gnomad FIN exome AF: 0.962

Gnomad NFE exome AF: 0.947

Gnomad OTH exome AF: 0.959

GnomAD4 exome AF: 0.948 AC: 1325338 AN: 1398186 Hom.: 628456 Cov.: 45 AF XY: 0.948 AC XY: 654069 AN XY: 689624

Gnomad4 AFR exome AF: 0.877

Gnomad4 AMR exome AF: 0.971

Gnomad4 ASJ exome AF: 0.986

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.952

Gnomad4 FIN exome AF: 0.962

Gnomad4 NFE exome AF: 0.946

Gnomad4 OTH exome AF: 0.948

GnomAD4 genome AF: 0.933 AC: 141059 AN: 151156 Hom.: 65940 Cov.: 25 AF XY: 0.935 AC XY: 68943 AN XY: 73772

Gnomad4 AFR AF: 0.882

Gnomad4 AMR AF: 0.954

Gnomad4 ASJ AF: 0.985

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.950

Gnomad4 FIN AF: 0.960

Gnomad4 NFE AF: 0.947

Gnomad4 OTH AF: 0.946

Alfa AF: 0.948 Hom.: 149730

Bravo AF: 0.932

TwinsUK AF: 0.943 AC: 3497

ALSPAC AF: 0.947 AC: 3651

ESP6500AA AF: 0.872 AC: 1207

ESP6500EA AF: 0.946 AC: 3010

ExAC AF: 0.944 AC: 22356

Asia WGS AF: 0.967 AC: 3362 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.034
Dann	Benign	0.68
DEOGEN2	Benign	0.0066	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.45	T;.
MetaRNN	Benign	0.0000010	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.13	N;N
REVEL	Benign	0.0040
Sift	Benign	0.20	T;T
Polyphen		0.0010	B;B
Vest4		0.026
MPC		0.082
ClinPred		0.0030	T
GERP RS		-5.8
Varity_R		0.027
gMVP		0.14

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: rs4832089; hg19: chr2-84756049;