NM_004448.4:c.1947-542A>G

Variant names:

• chr17-39722777-A-G
• rs2088126
• NM_004448.4:c.1947-542A>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.1947-542A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 151,436 control chromosomes in the GnomAD database, including 31,977 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 0.65 (31977 hom., cov: 28)
• Consequence: ERBB2 NM_004448.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.840
• Publications: 7 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=-1.03).
• 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.1947-542A>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.1947-542A>G		intron_variant	Intron 16 of 26	1	NM_004448.4	ENSP00000269571.4

Frequencies

GnomAD3 genomes AF: 0.646 AC: 97690 AN: 151320 Hom.: 31938 Cov.: 28

Gnomad AFR AF: 0.598

Gnomad AMI AF: 0.791

Gnomad AMR AF: 0.593

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.710

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.633

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

GnomAD4 genome AF: 0.646 AC: 97791 AN: 151436 Hom.: 31977 Cov.: 28 AF XY: 0.644 AC XY: 47675 AN XY: 73988

African (AFR) AF: 0.599 AC: 24668 AN: 41192

American (AMR) AF: 0.593 AC: 9024 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 2427 AN: 3464

East Asian (EAS) AF: 0.399 AC: 2054 AN: 5144

South Asian (SAS) AF: 0.732 AC: 3505 AN: 4786

European-Finnish (FIN) AF: 0.709 AC: 7445 AN: 10500

Middle Eastern (MID) AF: 0.695 AC: 203 AN: 292

European-Non Finnish (NFE) AF: 0.684 AC: 46412 AN: 67838

Other (OTH) AF: 0.635 AC: 1335 AN: 2104

Alfa AF: 0.653 Hom.: 3996

Bravo AF: 0.630

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.51
PhyloP100		-0.84
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: rs2088126; hg19: chr17-37879030;