chr17-39723509-G-A

Variant names:

• chr17-39723509-G-A
• rs903506
• NM_004448.4:c.2086-29G>A

Variant summary

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

The NM_004448.4(ERBB2):​c.2086-29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 1,612,328 control chromosomes in the GnomAD database, including 340,565 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 0.52 (23657 hom., cov: 32)
  • Exomes 𝑓: 0.65 (316908 hom.)
• Consequence: ERBB2 NM_004448.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• 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)

ENSG00000305964 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_004448.4	c.2086-29G>A		intron_variant	Intron 17 of 26	ENST00000269571.10	NP_004439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10	c.2086-29G>A		intron_variant	Intron 17 of 26	1	NM_004448.4	ENSP00000269571.4

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79326 AN: 152052 Hom.: 23648 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.773

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.540

GnomAD2 exomes AF: 0.610 AC: 150465 AN: 246764 AF XY: 0.626

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.570

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.365

Gnomad FIN exome AF: 0.684

Gnomad NFE exome AF: 0.672

Gnomad OTH exome AF: 0.636

GnomAD4 exome AF: 0.653 AC: 954101 AN: 1460158 Hom.: 316908 Cov.: 67 AF XY: 0.656 AC XY: 476579 AN XY: 726268

African (AFR) AF: 0.220 AC: 7362 AN: 33462

American (AMR) AF: 0.566 AC: 25139 AN: 44404

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 17893 AN: 26098

East Asian (EAS) AF: 0.441 AC: 17477 AN: 39628

South Asian (SAS) AF: 0.694 AC: 59808 AN: 86154

European-Finnish (FIN) AF: 0.677 AC: 35966 AN: 53148

Middle Eastern (MID) AF: 0.705 AC: 4033 AN: 5720

European-Non Finnish (NFE) AF: 0.674 AC: 748610 AN: 1111230

Other (OTH) AF: 0.627 AC: 37813 AN: 60314

GnomAD4 genome AF: 0.521 AC: 79349 AN: 152170 Hom.: 23657 Cov.: 32 AF XY: 0.521 AC XY: 38779 AN XY: 74404

African (AFR) AF: 0.228 AC: 9460 AN: 41530

American (AMR) AF: 0.530 AC: 8104 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 2352 AN: 3472

East Asian (EAS) AF: 0.394 AC: 2035 AN: 5164

South Asian (SAS) AF: 0.660 AC: 3180 AN: 4816

European-Finnish (FIN) AF: 0.681 AC: 7222 AN: 10600

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.661 AC: 44968 AN: 67980

Other (OTH) AF: 0.541 AC: 1144 AN: 2116

Alfa AF: 0.577 Hom.: 5978

Bravo AF: 0.494

Asia WGS AF: 0.559 AC: 1943 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.34
DANN	Benign	0.88
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs903506; hg19: chr17-37879762; COSMIC: COSV54069307; COSMIC: COSV54069307;