rs121913468

Variant names:

• chr17-39724008-G-A
• rs121913468
• NM_004448.4:c.2305G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-39724008-G-A
• chr17-39724008-G-C
• chr17-39724008-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_004448.4(ERBB2):​c.2305G>A​(p.Asp769Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ERBB2 NM_004448.4 missense, splice_region
• Scores: Splicing: ADA: 0.7214
• Clinical Significance: Likely pathogenic no assertion criteria provided P:5
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ERBB2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 3.2497 (above the threshold of 3.09). Trascript score misZ: 4.234 (above the threshold of 3.09). GenCC associations: The gene is linked to visceral neuropathy, familial, 2, autosomal recessive, lung cancer, Hirschsprung disease, glioma susceptibility 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_004448.4	c.2305G>A	p.Asp769Asn	missense_variant, splice_region_variant	Exon 19 of 27	ENST00000269571.10	NP_004439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10	c.2305G>A	p.Asp769Asn	missense_variant, splice_region_variant	Exon 19 of 27	1	NM_004448.4	ENSP00000269571.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: no assertion criteria provided

Submissions by phenotype

Carcinoma of esophagus Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Gastric adenocarcinoma Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Breast neoplasm Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Transitional cell carcinoma of the bladder Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neoplasm of uterine cervix Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	.;.;.;D;.;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	-0.17	.;.;.;.;.;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.4	.;D;D;D;.;D
REVEL	Uncertain	0.56
Sift	Benign	0.033	.;D;D;D;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		1.0	.;.;D;D;.;D
Vest4		0.68
MutPred		0.41		.;.;.;.;Loss of phosphorylation at Y772 (P = 0.0707);Loss of phosphorylation at Y772 (P = 0.0707);
MVP		0.77
MPC		2.4
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.64
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.72
dbscSNV1_RF	Pathogenic	0.73
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

Publications

LitVar

Other links and lift over

dbSNP: rs121913468; hg19: chr17-37880261; COSMIC: COSV54063143; COSMIC: COSV54063143;