rs28375417

Positions:

• chr2-84653321-G-A
• chr2-84653321-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001370.2(DNAH6):​c.5081G>A​(p.Gly1694Glu) 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. 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.

• 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

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.5081G>A	p.Gly1694Glu	missense_variant, splice_region_variant	34/77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.5081G>A	p.Gly1694Glu	missense_variant, splice_region_variant	34/77	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: 0.00 AC XY: 0 AN XY: 663826

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.45e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D;.
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.7	H;H
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0040	D;D
Polyphen		0.99	D;D
Vest4		0.66
MutPred		0.51		Loss of glycosylation at S1693 (P = 0.0487);Loss of glycosylation at S1693 (P = 0.0487);
MVP		0.48
MPC		0.47
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.77
gMVP		0.82

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: rs28375417; hg19: chr2-84880445;