rs200815756

Variant names:

• chr6-38734507-G-A
• rs200815756
• NM_001206927.2:c.644G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001206927.2(DNAH8):​c.644G>A​(p.Gly215Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000346 in 1,613,620 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.51

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08723989).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.644G>A	p.Gly215Glu	missense_variant	Exon 5 of 93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.644G>A	p.Gly215Glu	missense_variant	Exon 5 of 93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000373278.8	c.644G>A	p.Gly215Glu	missense_variant	Exon 5 of 5	1		ENSP00000362375.4
DNAH8	ENST00000449981.6	c.644G>A	p.Gly215Glu	missense_variant	Exon 4 of 82	5		ENSP00000415331.2
DNAH8	ENST00000359357	c.-8G>A		5_prime_UTR_variant	Exon 3 of 91	2		ENSP00000352312.3

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000446 AC: 112 AN: 251058 Hom.: 0 AF XY: 0.000509 AC XY: 69 AN XY: 135686

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000726

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000713

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000350 AC: 512 AN: 1461550 Hom.: 1 Cov.: 32 AF XY: 0.000362 AC XY: 263 AN XY: 727080

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000851

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000410

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74260

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000534 Hom.: 1

Bravo AF: 0.000487

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00124

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 215 of the DNAH8 protein (p.Gly215Glu). This variant is present in population databases (rs200815756, gnomAD 0.06%). 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: 576883). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Benign	0.57
DEOGEN2	Benign	0.0075	T;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.087	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	.;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0070	.;D;T
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		1.0	.;D;.
Vest4		0.72
MVP		0.31
ClinPred		0.086	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.63

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: rs200815756; hg19: chr6-38702283;