chr12-56098868-G-C

Variant names:

• chr12-56098868-G-C
• rs193920754
• NM_001982.4:c.2802G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001982.4(ERBB3):​c.2802G>C​(p.Gln934His) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ERBB3 NM_001982.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.477
• Publications: 6 publications found

Genes affected

ERBB3 (HGNC:3431): (erb-b2 receptor tyrosine kinase 3) This gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. This membrane-bound protein has a neuregulin binding domain but not an active kinase domain. It therefore can bind this ligand but not convey the signal into the cell through protein phosphorylation. However, it does form heterodimers with other EGF receptor family members which do have kinase activity. Heterodimerization leads to the activation of pathways which lead to cell proliferation or differentiation. Amplification of this gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors. Alternate transcriptional splice variants encoding different isoforms have been characterized. One isoform lacks the intermembrane region and is secreted outside the cell. This form acts to modulate the activity of the membrane-bound form. Additional splice variants have also been reported, but they have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

ERBB3 Gene-Disease associations (from GenCC):

• lethal congenital contracture syndrome 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• visceral neuropathy, familial, 1, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: G2P
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34262764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.2802G>C	p.Gln934His	missense_variant	Exon 23 of 28	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.2625G>C	p.Gln875His	missense_variant	Exon 23 of 28		XP_047284456.1
ERBB3	XM_047428501.1	c.2625G>C	p.Gln875His	missense_variant	Exon 23 of 28		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8	c.2802G>C	p.Gln934His	missense_variant	Exon 23 of 28	1	NM_001982.4	ENSP00000267101.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Prostate cancer Uncertain:1

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Science for Life laboratory, Karolinska Institutet

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;D;D;D
Eigen	Benign	0.076
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.86	D;D;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.1	L;.;.;.;.
PhyloP100		0.48
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	N;N;.;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.10	T;T;.;T;T
Sift4G	Uncertain	0.046	D;D;T;T;T
Polyphen		0.020	B;B;.;.;P
Vest4		0.28
MutPred		0.52		Gain of disorder (P = 0.1896);.;.;.;.;
MVP		0.86
MPC		0.34
ClinPred		0.35	T
GERP RS		6.2
Varity_R		0.38
gMVP		0.71
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs193920754; hg19: chr12-56492652; COSMIC: COSV57257892; COSMIC: COSV57257892;