NM_004448.4:c.1963A>G

Variant names:

• chr17-39723335-A-G
• rs1136201
• NM_004448.4:c.1963A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004448.4(ERBB2):​c.1963A>G​(p.Ile655Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,611,762 control chromosomes in the GnomAD database, including 42,083 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2846 hom., cov: 31)
  • Exomes 𝑓: 0.23 (39237 hom.)
• Consequence: ERBB2 NM_004448.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 3.57
• Publications: 293 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013844967).
• BP6: Variant 17-39723335-A-G is Benign according to our data. Variant chr17-39723335-A-G is described in ClinVar as Benign. ClinVar VariationId is 13873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004448.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB2	NM_004448.4	MANE Select	c.1963A>G	p.Ile655Val	missense	Exon 17 of 27	NP_004439.2	P04626-1
	ERBB2	NM_001382784.1		c.2080A>G	p.Ile694Val	missense	Exon 18 of 28	NP_001369713.1
	ERBB2	NM_001382785.1		c.2065A>G	p.Ile689Val	missense	Exon 18 of 28	NP_001369714.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB2	ENST00000269571.10	TSL:1 MANE Select	c.1963A>G	p.Ile655Val	missense	Exon 17 of 27	ENSP00000269571.4	P04626-1
	ERBB2	ENST00000584450.5	TSL:1	c.1963A>G	p.Ile655Val	missense	Exon 17 of 26	ENSP00000463714.1	J3QLU9
	ERBB2	ENST00000578373.5	TSL:1	n.*1753A>G		non_coding_transcript_exon	Exon 17 of 27	ENSP00000463427.1	J3QL83

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26137 AN: 149944 Hom.: 2844 Cov.: 31

Gnomad AFR AF: 0.0440

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.196 AC: 49359 AN: 251376 AF XY: 0.198

Gnomad AFR exome AF: 0.0403

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.226 AC: 329782 AN: 1461700 Hom.: 39237 Cov.: 45 AF XY: 0.223 AC XY: 162492 AN XY: 727148

African (AFR) AF: 0.0352 AC: 1179 AN: 33476

American (AMR) AF: 0.158 AC: 7058 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3714 AN: 26126

East Asian (EAS) AF: 0.126 AC: 5014 AN: 39690

South Asian (SAS) AF: 0.157 AC: 13524 AN: 86250

European-Finnish (FIN) AF: 0.297 AC: 15872 AN: 53406

Middle Eastern (MID) AF: 0.133 AC: 764 AN: 5766

European-Non Finnish (NFE) AF: 0.243 AC: 270510 AN: 1111878

Other (OTH) AF: 0.201 AC: 12147 AN: 60392

GnomAD4 genome AF: 0.174 AC: 26140 AN: 150062 Hom.: 2846 Cov.: 31 AF XY: 0.176 AC XY: 12858 AN XY: 73220

African (AFR) AF: 0.0439 AC: 1785 AN: 40662

American (AMR) AF: 0.167 AC: 2511 AN: 15078

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 478 AN: 3444

East Asian (EAS) AF: 0.126 AC: 642 AN: 5086

South Asian (SAS) AF: 0.156 AC: 723 AN: 4634

European-Finnish (FIN) AF: 0.303 AC: 3133 AN: 10328

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.241 AC: 16256 AN: 67536

Other (OTH) AF: 0.161 AC: 337 AN: 2092

Alfa AF: 0.209 Hom.: 10693

Bravo AF: 0.156

TwinsUK AF: 0.222 AC: 823

ALSPAC AF: 0.238 AC: 917

ESP6500AA AF: 0.0481 AC: 212

ESP6500EA AF: 0.230 AC: 1980

ExAC AF: 0.196 AC: 23831

Asia WGS AF: 0.152 AC: 528 AN: 3478

EpiCase AF: 0.222

EpiControl AF: 0.214

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ERBB2 POLYMORPHISM (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.020
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	0.81	T
Polyphen		0.68	P
Vest4		0.068
MPC		1.1
ClinPred		0.017	T
GERP RS		5.0
Varity_R		0.18
gMVP		0.50
Mutation Taster		=88/12	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: rs1136201; hg19: chr17-37879588; COSMIC: COSV54062262; COSMIC: COSV54062262;