rs55943169

chr17-39727923-C-Achr17-39727923-C-Gchr17-39727923-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004448.4(ERBB2):c.3647C>A(p.Ala1216Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00726 in 1,614,188 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. A1216A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0056 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (59 hom.)
• Consequence: ERBB2 NM_004448.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 2.88

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ERBB2
• BP4: Computational evidence support a benign effect (MetaRNN=0.008421838).
• BP6: Variant 17-39727923-C-A is Benign according to our data. Variant chr17-39727923-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 134084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00559 (851/152354) while in subpopulation NFE AF= 0.00783 (533/68032). AF 95% confidence interval is 0.00728. There are 6 homozygotes in gnomad4. There are 437 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB2	NM_004448.4	c.3647C>A	p.Ala1216Asp	missense_variant	27/27	ENST00000269571.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB2	ENST00000269571.10	c.3647C>A	p.Ala1216Asp	missense_variant	27/27	1	NM_004448.4	P1

Frequencies

GnomAD3 genomes AF: 0.00559 AC: 851 AN: 152236 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00783

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00566 AC: 1421 AN: 250928 Hom.: 6 AF XY: 0.00551 AC XY: 748 AN XY: 135834

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00647

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.00772

Gnomad OTH exome AF: 0.00604

GnomAD4 exome AF: 0.00743 AC: 10865 AN: 1461834 Hom.: 59 Cov.: 34 AF XY: 0.00726 AC XY: 5281 AN XY: 727228

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00643

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.00837

Gnomad4 OTH exome AF: 0.00556

GnomAD4 genome AF: 0.00559 AC: 851 AN: 152354 Hom.: 6 Cov.: 32 AF XY: 0.00587 AC XY: 437 AN XY: 74504

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0194

Gnomad4 NFE AF: 0.00783

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00682 Hom.: 9

Bravo AF: 0.00413

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00536 AC: 651

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00698

EpiControl AF: 0.00652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ERBB2: PP3, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.97	D
MetaRNN	Benign	0.0084	T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		1.0, 0.22, 0.028	.;.;D;B;B
Vest4		0.49
MVP		0.74
MPC		1.4
ClinPred		0.031	T
GERP RS		4.4
Varity_R		0.45
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55943169; hg19: chr17-37884176; COSMIC: COSV99059727; COSMIC: COSV99059727;