2-84653321-G-T

Variant names:

• chr2-84653321-G-T
• rs28375417
• NM_001370.2:c.5081G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001370.2(DNAH6):​c.5081G>T​(p.Gly1694Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000738 in 1,354,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1694A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: DNAH6 NM_001370.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.5081G>T	p.Gly1694Val	missense_variant, splice_region_variant	Exon 34 of 77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.5081G>T	p.Gly1694Val	missense_variant, splice_region_variant	Exon 34 of 77	5	NM_001370.2	ENSP00000374045.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1354644 Hom.: 0 Cov.: 31 AF XY: 0.00000151 AC XY: 1 AN XY: 663826

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29534

American (AMR) AF: 0.00 AC: 0 AN: 27222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22750

East Asian (EAS) AF: 0.00 AC: 0 AN: 35238

South Asian (SAS) AF: 0.0000137 AC: 1 AN: 72912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5450

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1057746

Other (OTH) AF: 0.00 AC: 0 AN: 55940

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;.
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	-0.041	T
MutationAssessor	Pathogenic	4.0	H;H
PhyloP100		6.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0040	D;D
Polyphen		0.99	D;D
Vest4		0.74
MutPred		0.53		Loss of glycosylation at S1693 (P = 0.0415);Loss of glycosylation at S1693 (P = 0.0415);
MVP		0.54
MPC		0.43
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.76
gMVP		0.75
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs28375417; hg19: chr2-84880445;