2-108897198-G-C

Variant names:

• chr2-108897198-G-C
• rs12623957
• NM_022336.4:c.1056C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_022336.4(EDAR):​c.1056C>G​(p.Cys352Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C352C) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDAR NM_022336.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• Publications: 23 publications found

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]

RANBP2 Gene-Disease associations (from GenCC):

• familial acute necrotizing encephalopathy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 34 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.72828 (below the threshold of 3.09). Trascript score misZ: 1.2871 (below the threshold of 3.09). GenCC associations: The gene is linked to ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive, ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant, autosomal dominant hypohidrotic ectodermal dysplasia, autosomal recessive hypohidrotic ectodermal dysplasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDAR	NM_022336.4	c.1056C>G	p.Cys352Trp	missense_variant	Exon 12 of 12	ENST00000258443.7	NP_071731.1
EDAR	XM_006712204.2	c.1152C>G	p.Cys384Trp	missense_variant	Exon 11 of 11		XP_006712267.1
RANBP2	XM_047445367.1	c.8370+124152G>C		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.1056C>G	p.Cys352Trp	missense_variant	Exon 12 of 12	1	NM_022336.4	ENSP00000258443.2
EDAR	ENST00000376651.1	c.1152C>G	p.Cys384Trp	missense_variant	Exon 11 of 11	2		ENSP00000365839.1
EDAR	ENST00000409271.5	c.1152C>G	p.Cys384Trp	missense_variant	Exon 12 of 12	2		ENSP00000386371.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	.;D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.2	.;M;.
PhyloP100		1.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.74
MutPred		0.49		.;Loss of catalytic residue at L353 (P = 0.0139);.;
MVP		0.97
MPC		1.2
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.82
gMVP		0.90
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs12623957; hg19: chr2-109513654;