rs151195196

Variant names:

• chr2-108930972-C-G
• NM_022336.4:c.43G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-108930972-C-G
• chr2-108930972-C-T

Variant summary

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

The NM_022336.4(EDAR):​c.43G>C​(p.Val15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: EDAR NM_022336.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180

Genes affected

EDAR (HGNC:2895): (ectodysplasin A receptor) This gene encodes a member of the tumor necrosis factor receptor family. The encoded transmembrane protein is a receptor for the soluble ligand ectodysplasin A, and can activate the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways. It is required for the development of hair, teeth, and other ectodermal derivatives. Mutations in this gene result in autosomal dominant and recessive forms of hypohidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]

RANBP2 (HGNC:9848): (RAN binding protein 2) RAN is a small GTP-binding protein of the RAS superfamily that is associated with the nuclear membrane and is thought to control a variety of cellular functions through its interactions with other proteins. This gene encodes a very large RAN-binding protein that immunolocalizes to the nuclear pore complex. The protein is a giant scaffold and mosaic cyclophilin-related nucleoporin implicated in the Ran-GTPase cycle. The encoded protein directly interacts with the E2 enzyme UBC9 and strongly enhances SUMO1 transfer from UBC9 to the SUMO1 target SP100. These findings place sumoylation at the cytoplasmic filaments of the nuclear pore complex and suggest that, for some substrates, modification and nuclear import are linked events. This gene is partially duplicated in a gene cluster that lies in a hot spot for recombination on chromosome 2q. [provided by RefSeq, Jul 2008]

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=0.15276486).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDAR	NM_022336.4	c.43G>C	p.Val15Leu	missense_variant	Exon 2 of 12	ENST00000258443.7	NP_071731.1
EDAR	XM_006712204.2	c.43G>C	p.Val15Leu	missense_variant	Exon 2 of 11		XP_006712267.1
RANBP2	XM_047445367.1	c.8370+157926C>G		intron_variant	Intron 24 of 24		XP_047301323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDAR	ENST00000258443.7	c.43G>C	p.Val15Leu	missense_variant	Exon 2 of 12	1	NM_022336.4	ENSP00000258443.2
EDAR	ENST00000376651.1	c.43G>C	p.Val15Leu	missense_variant	Exon 2 of 11	2		ENSP00000365839.1
EDAR	ENST00000409271.5	c.43G>C	p.Val15Leu	missense_variant	Exon 3 of 12	2		ENSP00000386371.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461644 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727138

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.96
DANN	Benign	0.94
DEOGEN2	Benign	0.29	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.74	.;T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.0	L;L;L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.21	N;N;N
REVEL	Benign	0.092
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0070	.;B;.
Vest4		0.35
MutPred		0.33		Gain of glycosylation at P14 (P = 0.1642);Gain of glycosylation at P14 (P = 0.1642);Gain of glycosylation at P14 (P = 0.1642);
MVP		0.77
MPC		0.29
ClinPred		0.085	T
GERP RS		-0.035
Varity_R		0.047
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-109547428;