2-211383796-G-T

Variant names:

• chr2-211383796-G-T
• NM_005235.3:c.3746C>A

Variant summary

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

The NM_005235.3(ERBB4):​c.3746C>A​(p.Pro1249His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERBB4 NM_005235.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08

Genes affected

ERBB4 (HGNC:3432): (erb-b2 receptor tyrosine kinase 4) This gene is a member of the Tyr protein kinase family and the epidermal growth factor receptor subfamily. It encodes a single-pass type I membrane protein with multiple cysteine rich domains, a transmembrane domain, a tyrosine kinase domain, a phosphotidylinositol-3 kinase binding site and a PDZ domain binding motif. The protein binds to and is activated by neuregulins and other factors and induces a variety of cellular responses including mitogenesis and differentiation. Multiple proteolytic events allow for the release of a cytoplasmic fragment and an extracellular fragment. Mutations in this gene have been associated with cancer. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.3746C>A	p.Pro1249His	missense_variant	Exon 28 of 28	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.3746C>A	p.Pro1249His	missense_variant	Exon 28 of 28	1	NM_005235.3	ENSP00000342235.4
ERBB4	ENST00000436443.5	c.3698C>A	p.Pro1233His	missense_variant	Exon 27 of 27	1		ENSP00000403204.1
ERBB4	ENST00000260943.11	c.3668C>A	p.Pro1223His	missense_variant	Exon 27 of 27	5		ENSP00000260943.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;D;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.85	.;L;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.2	.;D;D
REVEL	Uncertain	0.41
Sift	Benign	0.46	.;T;T
Sift4G	Benign	0.41	.;T;T
Polyphen		1.0, 1.0	.;D;D
Vest4		0.37, 0.37
MutPred		0.34		.;Loss of catalytic residue at P1248 (P = 0.0185);.;
MVP		0.75
MPC		0.39
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.48
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-212248521; COSMIC: COSV61505214;