rs141116145

chr17-39715294-C-Achr17-39715294-C-Gchr17-39715294-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_004448.4(ERBB2):c.1157C>A(p.Ala386Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,613,984 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (22 hom.)
• Consequence: ERBB2 NM_004448.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.260

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 -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ERBB2
• BP4: Computational evidence support a benign effect (MetaRNN=0.005045682).
• BP6: Variant 17-39715294-C-A is Benign according to our data. Variant chr17-39715294-C-A is described in ClinVar as [Benign]. Clinvar id is 134068.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-39715294-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00334 (509/152284) while in subpopulation AMR AF= 0.00621 (95/15304). AF 95% confidence interval is 0.0052. There are 3 homozygotes in gnomad4. There are 225 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB2	NM_004448.4	c.1157C>A	p.Ala386Asp	missense_variant	10/27	ENST00000269571.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB2	ENST00000269571.10	c.1157C>A	p.Ala386Asp	missense_variant	10/27	1	NM_004448.4	P1

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 509 AN: 152166 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00488

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00379 AC: 951 AN: 250936 Hom.: 5 AF XY: 0.00387 AC XY: 525 AN XY: 135642

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00472

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00547

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00404 AC: 5904 AN: 1461700 Hom.: 22 Cov.: 32 AF XY: 0.00396 AC XY: 2877 AN XY: 727124

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00512

Gnomad4 ASJ exome AF: 0.00444

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00109

Gnomad4 FIN exome AF: 0.00180

Gnomad4 NFE exome AF: 0.00459

Gnomad4 OTH exome AF: 0.00341

GnomAD4 genome AF: 0.00334 AC: 509 AN: 152284 Hom.: 3 Cov.: 32 AF XY: 0.00302 AC XY: 225 AN XY: 74458

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00488

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00501 Hom.: 7

Bravo AF: 0.00377

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00570 AC: 49

ExAC AF: 0.00345 AC: 419

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00800

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 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	Benign	0.091
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	15
Dann	Benign	0.93
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.20	N
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0050	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
Sift4G	Benign	0.16	T;T;T;T;T;T;T
Polyphen		0.0	.;B;.;B;B;.;B
Vest4		0.25
MVP		0.39
MPC		0.52
ClinPred		0.0084	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.32
gMVP		0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs141116145; hg19: chr17-37871547; COSMIC: COSV99507790; COSMIC: COSV99507790;