rs17025409

Positions:

• chr2-84670377-A-G

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.6356A>G​(p.Tyr2119Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,543,308 control chromosomes in the GnomAD database, including 633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (50 hom., cov: 33)
  • Exomes 𝑓: 0.024 (583 hom.)
• Consequence: DNAH6 NM_001370.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.57

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=0.0058374703).
• BP6: Variant 2-84670377-A-G is Benign according to our data. Variant chr2-84670377-A-G is described in ClinVar as [Benign]. Clinvar id is 402739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.054 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH6	NM_001370.2	c.6356A>G	p.Tyr2119Cys	missense_variant	39/77	ENST00000389394.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH6	ENST00000389394.8	c.6356A>G	p.Tyr2119Cys	missense_variant	39/77	5	NM_001370.2	P1
DNAH6	ENST00000602588.1	n.584A>G		non_coding_transcript_exon_variant	4/11	1

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3303 AN: 152212 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0361

Gnomad ASJ AF: 0.0446

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.0594

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0226

Gnomad OTH AF: 0.0354

GnomAD3 exomes AF: 0.0269 AC: 4126 AN: 153544 Hom.: 83 AF XY: 0.0294 AC XY: 2382 AN XY: 81036

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.0262

Gnomad ASJ exome AF: 0.0469

Gnomad EAS exome AF: 0.00805

Gnomad SAS exome AF: 0.0575

Gnomad FIN exome AF: 0.00975

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0321

GnomAD4 exome AF: 0.0244 AC: 33895 AN: 1390978 Hom.: 583 Cov.: 28 AF XY: 0.0260 AC XY: 17841 AN XY: 686070

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.0270

Gnomad4 ASJ exome AF: 0.0480

Gnomad4 EAS exome AF: 0.0207

Gnomad4 SAS exome AF: 0.0609

Gnomad4 FIN exome AF: 0.00867

Gnomad4 NFE exome AF: 0.0218

Gnomad4 OTH exome AF: 0.0290

GnomAD4 genome AF: 0.0217 AC: 3305 AN: 152330 Hom.: 50 Cov.: 33 AF XY: 0.0223 AC XY: 1660 AN XY: 74488

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.0361

Gnomad4 ASJ AF: 0.0446

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.0597

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.0226

Gnomad4 OTH AF: 0.0364

Alfa AF: 0.0239 Hom.: 75

Bravo AF: 0.0218

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0195 AC: 75

ESP6500AA AF: 0.00939 AC: 13

ESP6500EA AF: 0.0236 AC: 75

ExAC AF: 0.0338 AC: 827

Asia WGS AF: 0.0390 AC: 134 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

Jan 09, 2019

This variant is associated with the following publications: (PMID: 29767709) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;.
MetaRNN	Benign	0.0058	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Uncertain	0.49
Sift	Benign	0.031	D;D
Polyphen		1.0	D;D
Vest4		0.34
MPC		0.20
ClinPred		0.019	T
GERP RS		5.1
Varity_R		0.30
gMVP		0.78

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: rs17025409; hg19: chr2-84897501;