rs1058808

Variant names:

• chr17-39727784-C-G
• rs1058808
• NM_004448.4:c.3508C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-39727784-C-G
• chr17-39727784-C-A
• chr17-39727784-C-T

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.3508C>G​(p.Pro1170Ala) variant causes a missense change. The variant allele was found at a frequency of 0.642 in 1,612,086 control chromosomes in the GnomAD database, including 341,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (23709 hom., cov: 32)
  • Exomes 𝑓: 0.65 (317939 hom.)
• Consequence: ERBB2 NM_004448.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 4.29
• Publications: 184 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=1.0380236E-5).
• BP6: Variant 17-39727784-C-G is Benign according to our data. Variant chr17-39727784-C-G is described in ClinVar as Benign. ClinVar VariationId is 134082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.658 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.3508C>G	p.Pro1170Ala	missense	Exon 27 of 27	NP_004439.2	P04626-1
	ERBB2	NM_001382784.1		c.3625C>G	p.Pro1209Ala	missense	Exon 28 of 28	NP_001369713.1
	ERBB2	NM_001382785.1		c.3610C>G	p.Pro1204Ala	missense	Exon 28 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.3508C>G	p.Pro1170Ala	missense	Exon 27 of 27	ENSP00000269571.4	P04626-1
	ERBB2	ENST00000584450.5	TSL:1	c.*87C>G		3_prime_UTR	Exon 26 of 26	ENSP00000463714.1	J3QLU9
	ERBB2	ENST00000578373.5	TSL:1	n.*3298C>G		non_coding_transcript_exon	Exon 27 of 27	ENSP00000463427.1	J3QL83

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79394 AN: 151918 Hom.: 23697 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.676

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.682

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.540

GnomAD2 exomes AF: 0.609 AC: 152231 AN: 249792 AF XY: 0.625

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.569

Gnomad ASJ exome AF: 0.689

Gnomad EAS exome AF: 0.366

Gnomad FIN exome AF: 0.682

Gnomad NFE exome AF: 0.673

Gnomad OTH exome AF: 0.634

GnomAD4 exome AF: 0.654 AC: 955482 AN: 1460050 Hom.: 317939 Cov.: 52 AF XY: 0.657 AC XY: 477227 AN XY: 726106

African (AFR) AF: 0.220 AC: 7376 AN: 33456

American (AMR) AF: 0.565 AC: 25214 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 17821 AN: 26020

East Asian (EAS) AF: 0.443 AC: 17569 AN: 39678

South Asian (SAS) AF: 0.694 AC: 59769 AN: 86064

European-Finnish (FIN) AF: 0.677 AC: 36119 AN: 53380

Middle Eastern (MID) AF: 0.702 AC: 4038 AN: 5756

European-Non Finnish (NFE) AF: 0.675 AC: 749705 AN: 1110778

Other (OTH) AF: 0.628 AC: 37871 AN: 60314

GnomAD4 genome AF: 0.522 AC: 79420 AN: 152036 Hom.: 23709 Cov.: 32 AF XY: 0.522 AC XY: 38817 AN XY: 74320

African (AFR) AF: 0.228 AC: 9459 AN: 41470

American (AMR) AF: 0.532 AC: 8128 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 2346 AN: 3470

East Asian (EAS) AF: 0.395 AC: 2027 AN: 5132

South Asian (SAS) AF: 0.661 AC: 3182 AN: 4814

European-Finnish (FIN) AF: 0.682 AC: 7220 AN: 10594

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.663 AC: 45034 AN: 67956

Other (OTH) AF: 0.541 AC: 1142 AN: 2112

Alfa AF: 0.632 Hom.: 10206

Bravo AF: 0.495

TwinsUK AF: 0.670 AC: 2486

ALSPAC AF: 0.667 AC: 2571

ESP6500AA AF: 0.234 AC: 1033

ESP6500EA AF: 0.657 AC: 5646

ExAC AF: 0.605 AC: 73474

Asia WGS AF: 0.559 AC: 1945 AN: 3478

EpiCase AF: 0.679

EpiControl AF: 0.672

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.000010	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.25
Sift	Benign	0.030	D
Sift4G	Benign	0.15	T
Polyphen		0.74	P
Vest4		0.17
MPC		0.93
ClinPred		0.034	T
GERP RS		5.0
Varity_R		0.12
gMVP		0.15
Mutation Taster		=60/40	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: rs1058808; hg19: chr17-37884037; COSMIC: COSV54064104; COSMIC: COSV54064104;