chr2-211562021-G-C

Variant names:

• chr2-211562021-G-C
• rs2125722041
• NM_005235.3:c.2369C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005235.3(ERBB4):​c.2369C>G​(p.Pro790Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 10.0

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

Our verdict: Uncertain_significance. The variant received 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.2369C>G	p.Pro790Arg	missense_variant	Exon 20 of 28	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.2369C>G	p.Pro790Arg	missense_variant	Exon 20 of 28	1	NM_005235.3	ENSP00000342235.4
ERBB4	ENST00000436443.5	c.2369C>G	p.Pro790Arg	missense_variant	Exon 20 of 27	1		ENSP00000403204.1
ERBB4	ENST00000484594.5	n.2421C>G		non_coding_transcript_exon_variant	Exon 20 of 20	1
ERBB4	ENST00000260943.11	c.2339C>G	p.Pro780Arg	missense_variant	Exon 20 of 27	5		ENSP00000260943.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.80	.;N;N
PhyloP100		10
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.2	.;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	.;D;D
Sift4G	Uncertain	0.016	.;D;D
Polyphen		1.0	.;D;D
Vest4		0.75, 0.77
MutPred		0.48		.;Gain of catalytic residue at P790 (P = 0.0179);Gain of catalytic residue at P790 (P = 0.0179);
MVP		0.78
MPC		0.53
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.86
gMVP		0.65
Mutation Taster		=7/93	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

Publications

LitVar

Other links and lift over

dbSNP: rs2125722041; hg19: chr2-212426746;