rs762397682

Variant names:

• chr6-38860533-A-G
• rs762397682
• NM_001206927.2:c.6035A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001206927.2(DNAH8):​c.6035A>G​(p.Asp2012Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,522,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000095 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

DNAH8 (HGNC:2952): (dynein axonemal heavy chain 8) The protein encoded by this gene is a heavy chain of an axonemal dynein involved in sperm and respiratory cilia motility. Axonemal dyneins generate force through hydrolysis of ATP and binding to microtubules. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.6035A>G	p.Asp2012Gly	missense_variant	Exon 43 of 93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.6035A>G	p.Asp2012Gly	missense_variant	Exon 43 of 93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.5384A>G	p.Asp1795Gly	missense_variant	Exon 41 of 91	2		ENSP00000352312.3
DNAH8	ENST00000449981.6	c.6035A>G	p.Asp2012Gly	missense_variant	Exon 42 of 82	5		ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000157 AC: 3 AN: 191572 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 105494

Gnomad AFR exome AF: 0.0000768

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000209

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000949 AC: 13 AN: 1370364 Hom.: 0 Cov.: 29 AF XY: 0.00000590 AC XY: 4 AN XY: 678388

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: 0.0000121

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74378

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Feb 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2012 of the DNAH8 protein (p.Asp2012Gly). This variant is present in population databases (rs762397682, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with DNAH8-related conditions. ClinVar contains an entry for this variant (Variation ID: 566971). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	3.3	.;.;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.4	.;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	.;D;D
Polyphen		1.0	.;.;D
Vest4		0.90
MutPred		0.49		.;.;Loss of stability (P = 0.0112);
MVP		0.80
MPC		0.65
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.83
gMVP		0.73

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: rs762397682; hg19: chr6-38828309;