rs2952156

Variant names:

• chr17-39720582-A-G
• rs2952156
• NM_004448.4:c.1946+748A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004448.4(ERBB2):​c.1946+748A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 152,030 control chromosomes in the GnomAD database, including 32,006 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.64 (32006 hom., cov: 32)
• Consequence: ERBB2 NM_004448.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.07
• Publications: 32 publications found

Genes affected

ERBB2 (HGNC:3430): (erb-b2 receptor tyrosine kinase 2) This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. [provided by RefSeq, Jul 2008]

ERBB2 Gene-Disease associations (from GenCC):

• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lung cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• glioma susceptibility 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• visceral neuropathy, familial, 2, autosomal recessive

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_004448.4	c.1946+748A>G		intron_variant	Intron 16 of 26	ENST00000269571.10	NP_004439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10	c.1946+748A>G		intron_variant	Intron 16 of 26	1	NM_004448.4	ENSP00000269571.4

Frequencies

GnomAD3 genomes AF: 0.645 AC: 97921 AN: 151912 Hom.: 31965 Cov.: 32

Gnomad AFR AF: 0.595

Gnomad AMI AF: 0.795

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.632

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.645 AC: 98025 AN: 152030 Hom.: 32006 Cov.: 32 AF XY: 0.643 AC XY: 47814 AN XY: 74310

African (AFR) AF: 0.596 AC: 24700 AN: 41448

American (AMR) AF: 0.592 AC: 9039 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 2428 AN: 3466

East Asian (EAS) AF: 0.402 AC: 2072 AN: 5156

South Asian (SAS) AF: 0.732 AC: 3529 AN: 4820

European-Finnish (FIN) AF: 0.708 AC: 7496 AN: 10590

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.684 AC: 46498 AN: 67964

Other (OTH) AF: 0.633 AC: 1339 AN: 2114

Alfa AF: 0.667 Hom.: 15822

Bravo AF: 0.629

Asia WGS AF: 0.633 AC: 2204 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.62
DANN	Benign	0.44
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2952156; hg19: chr17-37876835;