rs1192269

Variant names:

• chr2-84705712-G-A
• rs1192269
• NM_001370.2:c.8692G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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
• Publications: 8 publications found

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]

DNAH6 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH6	NM_001370.2	MANE Select	c.8692G>A	p.Val2898Ile	missense	Exon 52 of 77	NP_001361.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH6	ENST00000389394.8	TSL:5 MANE Select	c.8692G>A	p.Val2898Ile	missense	Exon 52 of 77	ENSP00000374045.3

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

GnomAD2 exomes AF: 0.0403 AC: 6304 AN: 156304 AF XY: 0.0418

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 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

African (AFR) AF: 0.0172 AC: 542 AN: 31468

American (AMR) AF: 0.0215 AC: 762 AN: 35412

Ashkenazi Jewish (ASJ) AF: 0.0146 AC: 366 AN: 25104

East Asian (EAS) AF: 0.000784 AC: 28 AN: 35722

South Asian (SAS) AF: 0.0639 AC: 5056 AN: 79102

European-Finnish (FIN) AF: 0.0387 AC: 1908 AN: 49358

Middle Eastern (MID) AF: 0.0393 AC: 223 AN: 5678

European-Non Finnish (NFE) AF: 0.0545 AC: 58792 AN: 1078594

Other (OTH) AF: 0.0459 AC: 2661 AN: 57980

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

African (AFR) AF: 0.0180 AC: 748 AN: 41504

American (AMR) AF: 0.0315 AC: 481 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3472

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5180

South Asian (SAS) AF: 0.0616 AC: 296 AN: 4806

European-Finnish (FIN) AF: 0.0408 AC: 433 AN: 10608

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0533 AC: 3625 AN: 68002

Other (OTH) AF: 0.0313 AC: 66 AN: 2112

Alfa AF: 0.0453 Hom.: 420

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.16
MPC		0.38
ClinPred		0.017	T
GERP RS		6.0
Varity_R		0.33
gMVP		0.47
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1192269; hg19: chr2-84932836; COSMIC: COSV107253961;