chr5-65992762-G-A

Variant names:

• chr5-65992762-G-A
• rs949907598
• NM_001253697.2:c.44G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001253697.2(ERBIN):​c.44G>A​(p.Arg15His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,612,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ERBIN NM_001253697.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.89

Genes affected

ERBIN (HGNC:15842): (erbb2 interacting protein) This gene is a member of the leucine-rich repeat and PDZ domain (LAP) family. The encoded protein contains 17 leucine-rich repeats and one PDZ domain. It binds to the unphosphorylated form of the ERBB2 protein and regulates ERBB2 function and localization. It has also been shown to affect the Ras signaling pathway by disrupting Ras-Raf interaction. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBIN	NM_001253697.2	c.44G>A	p.Arg15His	missense_variant	Exon 3 of 26	ENST00000284037.10	NP_001240626.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBIN	ENST00000284037.10	c.44G>A	p.Arg15His	missense_variant	Exon 3 of 26	1	NM_001253697.2	ENSP00000284037.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250014 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460240 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726360

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 15 of the ERBIN protein (p.Arg15His). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ERBIN-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T;.;T;.;.;.;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;.
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.8	D;D;N;D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.;.;D
Vest4		0.65
MutPred		0.46		Loss of MoRF binding (P = 0.0363);Loss of MoRF binding (P = 0.0363);Loss of MoRF binding (P = 0.0363);Loss of MoRF binding (P = 0.0363);Loss of MoRF binding (P = 0.0363);Loss of MoRF binding (P = 0.0363);Loss of MoRF binding (P = 0.0363);Loss of MoRF binding (P = 0.0363);
MVP		0.32
MPC		0.45
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.51

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: rs949907598; hg19: chr5-65288590; COSMIC: COSV99397214;