rs2229046

Variant names:

• chr12-56093417-T-C
• rs2229046
• NM_001982.4:c.1347T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001982.4(ERBB3):​c.1347T>C​(p.Ile449Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.074 in 1,613,794 control chromosomes in the GnomAD database, including 4,746 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (423 hom., cov: 31)
  • Exomes 𝑓: 0.074 (4323 hom.)
• Consequence: ERBB3 NM_001982.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.61
• Publications: 25 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-56093417-T-C is Benign according to our data. Variant chr12-56093417-T-C is described in ClinVar as Benign. ClinVar VariationId is 1269955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0745 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001982.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	NM_001982.4	MANE Select	c.1347T>C	p.Ile449Ile	synonymous	Exon 12 of 28	NP_001973.2	P21860-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	ENST00000267101.8	TSL:1 MANE Select	c.1347T>C	p.Ile449Ile	synonymous	Exon 12 of 28	ENSP00000267101.4	P21860-1
	ERBB3	ENST00000551242.5	TSL:1	n.988+4761T>C		intron	N/A	ENSP00000447510.1	P21860-3
	ERBB3	ENST00000926495.1		c.1347T>C	p.Ile449Ile	synonymous	Exon 13 of 29	ENSP00000596554.1

Frequencies

GnomAD3 genomes AF: 0.0730 AC: 11093 AN: 151984 Hom.: 422 Cov.: 31

Gnomad AFR AF: 0.0767

Gnomad AMI AF: 0.0890

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.0741

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0540

Gnomad FIN AF: 0.0998

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0761

Gnomad OTH AF: 0.0578

GnomAD2 exomes AF: 0.0646 AC: 16254 AN: 251420 AF XY: 0.0656

Gnomad AFR exome AF: 0.0786

Gnomad AMR exome AF: 0.0370

Gnomad ASJ exome AF: 0.0724

Gnomad EAS exome AF: 0.000870

Gnomad FIN exome AF: 0.0996

Gnomad NFE exome AF: 0.0768

Gnomad OTH exome AF: 0.0759

GnomAD4 exome AF: 0.0742 AC: 108389 AN: 1461692 Hom.: 4323 Cov.: 33 AF XY: 0.0736 AC XY: 53513 AN XY: 727146

African (AFR) AF: 0.0798 AC: 2672 AN: 33474

American (AMR) AF: 0.0394 AC: 1764 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0716 AC: 1871 AN: 26132

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39700

South Asian (SAS) AF: 0.0535 AC: 4614 AN: 86252

European-Finnish (FIN) AF: 0.0986 AC: 5265 AN: 53400

Middle Eastern (MID) AF: 0.0628 AC: 362 AN: 5768

European-Non Finnish (NFE) AF: 0.0788 AC: 87566 AN: 1111854

Other (OTH) AF: 0.0705 AC: 4256 AN: 60388

GnomAD4 genome AF: 0.0730 AC: 11102 AN: 152102 Hom.: 423 Cov.: 31 AF XY: 0.0740 AC XY: 5503 AN XY: 74342

African (AFR) AF: 0.0767 AC: 3184 AN: 41490

American (AMR) AF: 0.0613 AC: 937 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0741 AC: 257 AN: 3466

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5164

South Asian (SAS) AF: 0.0541 AC: 261 AN: 4826

European-Finnish (FIN) AF: 0.0998 AC: 1056 AN: 10576

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0761 AC: 5176 AN: 67986

Other (OTH) AF: 0.0567 AC: 120 AN: 2116

Alfa AF: 0.0725 Hom.: 276

Bravo AF: 0.0693

Asia WGS AF: 0.0250 AC: 86 AN: 3478

EpiCase AF: 0.0778

EpiControl AF: 0.0782

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.7
DANN	Benign	0.69
PhyloP100		-1.6
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	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: rs2229046; hg19: chr12-56487201; COSMIC: COSV57247825; COSMIC: COSV57247825;