rs2292238

Variant names:

• chr12-56100038-A-C
• rs2292238
• NM_001982.4:c.3129+9A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000267101.8(ERBB3):​c.3129+9A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,612,632 control chromosomes in the GnomAD database, including 122,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9193 hom., cov: 32)
  • Exomes 𝑓: 0.39 (113517 hom.)
• Consequence: ERBB3 ENST00000267101.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.18
• Publications: 28 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-56100038-A-C is Benign according to our data. Variant chr12-56100038-A-C is described in ClinVar as Benign. ClinVar VariationId is 1226099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000267101.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	NM_001982.4	MANE Select	c.3129+9A>C		intron	N/A	NP_001973.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	ENST00000267101.8	TSL:1 MANE Select	c.3129+9A>C		intron	N/A	ENSP00000267101.4
	ERBB3	ENST00000550070.6	TSL:1	c.1050+9A>C		intron	N/A	ENSP00000448946.2
	ERBB3	ENST00000551242.5	TSL:1	n.989-144A>C		intron	N/A	ENSP00000447510.1

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50818 AN: 151994 Hom.: 9179 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.346

GnomAD2 exomes AF: 0.365 AC: 91819 AN: 251364 AF XY: 0.365

Gnomad AFR exome AF: 0.185

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.337

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.391 AC: 570683 AN: 1460520 Hom.: 113517 Cov.: 35 AF XY: 0.389 AC XY: 282694 AN XY: 726604

African (AFR) AF: 0.179 AC: 6002 AN: 33450

American (AMR) AF: 0.377 AC: 16842 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 10616 AN: 26128

East Asian (EAS) AF: 0.342 AC: 13563 AN: 39694

South Asian (SAS) AF: 0.294 AC: 25357 AN: 86104

European-Finnish (FIN) AF: 0.392 AC: 20922 AN: 53410

Middle Eastern (MID) AF: 0.290 AC: 1672 AN: 5762

European-Non Finnish (NFE) AF: 0.408 AC: 452851 AN: 1110910

Other (OTH) AF: 0.379 AC: 22858 AN: 60348

GnomAD4 genome AF: 0.334 AC: 50874 AN: 152112 Hom.: 9193 Cov.: 32 AF XY: 0.332 AC XY: 24718 AN XY: 74366

African (AFR) AF: 0.186 AC: 7728 AN: 41490

American (AMR) AF: 0.359 AC: 5498 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1501 AN: 3472

East Asian (EAS) AF: 0.342 AC: 1766 AN: 5168

South Asian (SAS) AF: 0.294 AC: 1418 AN: 4820

European-Finnish (FIN) AF: 0.379 AC: 4016 AN: 10590

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27657 AN: 67956

Other (OTH) AF: 0.345 AC: 731 AN: 2116

Alfa AF: 0.373 Hom.: 6272

Bravo AF: 0.329

Asia WGS AF: 0.342 AC: 1189 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Lethal congenital contracture syndrome 2 (1)
-	-	1	Visceral neuropathy, familial (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.3
DANN	Benign	0.70
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs2292238; hg19: chr12-56493822; COSMIC: COSV57256344; COSMIC: COSV57256344;