rs1192269

Positions:

• chr2-84705712-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.8692G>A​(p.Val2898Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0491 in 1,550,596 control chromosomes in the GnomAD database, including 2,170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (153 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2017 hom.)
• Consequence: DNAH6 NM_001370.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.17

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 in gene, where missense usually causes diseases (based on misZ statistic), DNAH6. . Gene score misZ 3.5535 (greater than the threshold 3.09). Trascript score misZ 3.4022 (greater than threshold 3.09). GenCC has associacion of gene with male infertility with azoospermia or oligozoospermia due to single gene mutation.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0039929748).
• BP6: Variant 2-84705712-G-A is Benign according to our data. Variant chr2-84705712-G-A is described in ClinVar as [Benign]. Clinvar id is 402743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.8692G>A	p.Val2898Ile	missense_variant	52/77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.8692G>A	p.Val2898Ile	missense_variant	52/77	5	NM_001370.2	ENSP00000374045	P1

Frequencies

GnomAD3 genomes AF: 0.0382 AC: 5804 AN: 152060 Hom.: 153 Cov.: 32

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0613

Gnomad FIN AF: 0.0408

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0533

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0403 AC: 6304 AN: 156304 Hom.: 168 AF XY: 0.0418 AC XY: 3449 AN XY: 82608

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.0208

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.00131

Gnomad SAS exome AF: 0.0646

Gnomad FIN exome AF: 0.0380

Gnomad NFE exome AF: 0.0530

Gnomad OTH exome AF: 0.0415

GnomAD4 exome AF: 0.0503 AC: 70338 AN: 1398418 Hom.: 2017 Cov.: 32 AF XY: 0.0507 AC XY: 34950 AN XY: 689714

Gnomad4 AFR exome AF: 0.0172

Gnomad4 AMR exome AF: 0.0215

Gnomad4 ASJ exome AF: 0.0146

Gnomad4 EAS exome AF: 0.000784

Gnomad4 SAS exome AF: 0.0639

Gnomad4 FIN exome AF: 0.0387

Gnomad4 NFE exome AF: 0.0545

Gnomad4 OTH exome AF: 0.0459

GnomAD4 genome AF: 0.0381 AC: 5803 AN: 152178 Hom.: 153 Cov.: 32 AF XY: 0.0378 AC XY: 2810 AN XY: 74394

Gnomad4 AFR AF: 0.0180

Gnomad4 AMR AF: 0.0315

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0616

Gnomad4 FIN AF: 0.0408

Gnomad4 NFE AF: 0.0533

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0469 Hom.: 312

Bravo AF: 0.0353

TwinsUK AF: 0.0547 AC: 203

ALSPAC AF: 0.0506 AC: 195

ESP6500AA AF: 0.0210 AC: 29

ESP6500EA AF: 0.0515 AC: 164

ExAC AF: 0.0431 AC: 1076

Asia WGS AF: 0.0310 AC: 107 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;.
MetaRNN	Benign	0.0040	T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.92	N;N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.16
MPC		0.38
ClinPred		0.017	T
GERP RS		6.0
Varity_R		0.33
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1192269; hg19: chr2-84932836;