17-39723332-A-G

Variant names:

• chr17-39723332-A-G
• rs1801201
• NM_004448.4:c.1960A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004448.4(ERBB2):​c.1960A>G​(p.Ile654Val) variant causes a missense change. The variant allele was found at a frequency of 0.00808 in 1,607,662 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0084 (61 hom.)
• Consequence: ERBB2 NM_004448.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 4.53
• Publications: 47 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=0.003094107).
• BP6: Variant 17-39723332-A-G is Benign according to our data. Variant chr17-39723332-A-G is described in ClinVar as Benign. ClinVar VariationId is 13874.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 = 0.00515 (772/150010) while in subpopulation NFE AF = 0.00835 (564/67522). AF 95% confidence interval is 0.00778. There are 3 homozygotes in GnomAd4. There are 354 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 772 Unknown,AD gene.

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.1960A>G	p.Ile654Val	missense	Exon 17 of 27	NP_004439.2
	ERBB2	NM_001382784.1		c.2077A>G	p.Ile693Val	missense	Exon 18 of 28	NP_001369713.1
	ERBB2	NM_001382785.1		c.2062A>G	p.Ile688Val	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.1960A>G	p.Ile654Val	missense	Exon 17 of 27	ENSP00000269571.4
	ERBB2	ENST00000584450.5	TSL:1	c.1960A>G	p.Ile654Val	missense	Exon 17 of 26	ENSP00000463714.1
	ERBB2	ENST00000578373.5	TSL:1	n.*1750A>G		non_coding_transcript_exon	Exon 17 of 27	ENSP00000463427.1

Frequencies

GnomAD3 genomes AF: 0.00515 AC: 772 AN: 149896 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00430

Gnomad ASJ AF: 0.00232

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00171

Gnomad FIN AF: 0.000883

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00835

Gnomad OTH AF: 0.00771

GnomAD2 exomes AF: 0.00490 AC: 1231 AN: 251420 AF XY: 0.00480

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00824

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00838 AC: 12215 AN: 1457652 Hom.: 61 Cov.: 37 AF XY: 0.00810 AC XY: 5876 AN XY: 725238

African (AFR) AF: 0.00138 AC: 46 AN: 33364

American (AMR) AF: 0.00363 AC: 162 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00208 AC: 54 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39440

South Asian (SAS) AF: 0.00209 AC: 180 AN: 86216

European-Finnish (FIN) AF: 0.00177 AC: 93 AN: 52578

Middle Eastern (MID) AF: 0.00331 AC: 19 AN: 5748

European-Non Finnish (NFE) AF: 0.0102 AC: 11273 AN: 1109604

Other (OTH) AF: 0.00645 AC: 388 AN: 60118

GnomAD4 genome AF: 0.00515 AC: 772 AN: 150010 Hom.: 3 Cov.: 31 AF XY: 0.00484 AC XY: 354 AN XY: 73188

African (AFR) AF: 0.00221 AC: 90 AN: 40654

American (AMR) AF: 0.00430 AC: 65 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.00232 AC: 8 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.00171 AC: 8 AN: 4678

European-Finnish (FIN) AF: 0.000883 AC: 9 AN: 10196

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00835 AC: 564 AN: 67522

Other (OTH) AF: 0.00763 AC: 16 AN: 2098

Alfa AF: 0.00656 Hom.: 38

Bravo AF: 0.00549

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.00480 AC: 583

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00987

EpiControl AF: 0.00818

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ERBB2 POLYMORPHISM (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.0084
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.17	N
REVEL	Uncertain	0.33
Sift	Benign	0.16	T
Sift4G	Benign	0.36	T
Polyphen		0.12	B
Vest4		0.15
MVP		0.84
MPC		1.1
ClinPred		0.011	T
GERP RS		5.0
Varity_R		0.15
gMVP		0.70
Mutation Taster		=74/26	polymorphism

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: rs1801201; hg19: chr17-37879585; COSMIC: COSV54075144; COSMIC: COSV54075144;