rs141116145

Variant names:

• chr17-39715294-C-A
• rs141116145
• NM_004448.4:c.1157C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-39715294-C-A
• chr17-39715294-C-G
• chr17-39715294-C-T

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.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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.260
• Publications: 19 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 -20 ACMG points.

• 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/Likely_benign. ClinVar VariationId is 134068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 509 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.1157C>A	p.Ala386Asp	missense	Exon 10 of 27	NP_004439.2	P04626-1
	ERBB2	NM_001382784.1		c.1274C>A	p.Ala425Asp	missense	Exon 11 of 28	NP_001369713.1
	ERBB2	NM_001382785.1		c.1157C>A	p.Ala386Asp	missense	Exon 10 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.1157C>A	p.Ala386Asp	missense	Exon 10 of 27	ENSP00000269571.4	P04626-1
	ERBB2	ENST00000584450.5	TSL:1	c.1157C>A	p.Ala386Asp	missense	Exon 10 of 26	ENSP00000463714.1	J3QLU9
	ERBB2	ENST00000578199.5	TSL:1	c.1067C>A	p.Ala356Asp	missense	Exon 13 of 18	ENSP00000462808.1	F5H1T4

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

GnomAD2 exomes AF: 0.00379 AC: 951 AN: 250936 AF XY: 0.00387

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 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

African (AFR) AF: 0.000508 AC: 17 AN: 33478

American (AMR) AF: 0.00512 AC: 229 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00444 AC: 116 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00109 AC: 94 AN: 86244

European-Finnish (FIN) AF: 0.00180 AC: 96 AN: 53390

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5766

European-Non Finnish (NFE) AF: 0.00459 AC: 5102 AN: 1111900

Other (OTH) AF: 0.00341 AC: 206 AN: 60376

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

African (AFR) AF: 0.000794 AC: 33 AN: 41556

American (AMR) AF: 0.00621 AC: 95 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00488 AC: 332 AN: 68016

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00489 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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.26
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.036
Sift	Benign	0.16	T
Sift4G	Benign	0.16	T
Polyphen		0.0	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
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

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