NM_004448.4:c.1371A>G

Variant names:

• chr17-39715797-A-G
• rs2230698
• NM_004448.4:c.1371A>G
• ERBB2 p.Ser457Ser

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004448.4(ERBB2):​c.1371A>G​(p.Ser457Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00725 in 1,609,958 control chromosomes in the GnomAD database, including 692 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (356 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (336 hom.)
• Consequence: ERBB2 NM_004448.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.03
• Publications: 7 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)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-39715797-A-G is Benign according to our data. Variant chr17-39715797-A-G is described in ClinVar as Benign. ClinVar VariationId is 1168005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 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.1371A>G	p.Ser457Ser	synonymous	Exon 12 of 27	NP_004439.2	P04626-1
	ERBB2	NM_001382784.1		c.1488A>G	p.Ser496Ser	synonymous	Exon 13 of 28	NP_001369713.1
	ERBB2	NM_001382785.1		c.1371A>G	p.Ser457Ser	synonymous	Exon 12 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.1371A>G	p.Ser457Ser	synonymous	Exon 12 of 27	ENSP00000269571.4	P04626-1
	ERBB2	ENST00000584450.5	TSL:1	c.1371A>G	p.Ser457Ser	synonymous	Exon 12 of 26	ENSP00000463714.1	J3QLU9
	ERBB2	ENST00000578199.5	TSL:1	c.1281A>G	p.Ser427Ser	synonymous	Exon 15 of 18	ENSP00000462808.1	F5H1T4

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5611 AN: 152146 Hom.: 356 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0113 AC: 2814 AN: 248042 AF XY: 0.00832

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000435

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.00524

GnomAD4 exome AF: 0.00415 AC: 6049 AN: 1457694 Hom.: 336 Cov.: 32 AF XY: 0.00353 AC XY: 2561 AN XY: 725452

African (AFR) AF: 0.133 AC: 4468 AN: 33480

American (AMR) AF: 0.0142 AC: 636 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.000522 AC: 45 AN: 86258

European-Finnish (FIN) AF: 0.000588 AC: 29 AN: 49282

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.000269 AC: 299 AN: 1111988

Other (OTH) AF: 0.00909 AC: 549 AN: 60364

GnomAD4 genome AF: 0.0370 AC: 5627 AN: 152264 Hom.: 356 Cov.: 32 AF XY: 0.0356 AC XY: 2647 AN XY: 74454

African (AFR) AF: 0.127 AC: 5257 AN: 41530

American (AMR) AF: 0.0169 AC: 258 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68022

Other (OTH) AF: 0.0242 AC: 51 AN: 2108

Alfa AF: 0.0207 Hom.: 126

Bravo AF: 0.0427

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.094
DANN	Benign	0.41
PhyloP100		-4.0
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2230698;

hg19: chr17-37872050;

COSMIC: COSV54066034;