17-39700245-C-T

Variant names:

• chr17-39700245-C-T
• rs2058005545
• NM_004448.4:c.7C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001382783.1(ERBB2):​c.-209C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000774 in 1,292,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: ERBB2 NM_001382783.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.279
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BS2: High AC in GnomAdExome4 at 10 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382783.1. 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.7C>T	p.Leu3Leu	synonymous	Exon 1 of 27	NP_004439.2	P04626-1
	ERBB2	NM_001382783.1		c.-209C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 28	NP_001369712.1	P04626-5
	ERBB2	NM_001382784.1		c.7C>T	p.Leu3Leu	synonymous	Exon 1 of 28	NP_001369713.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB2	ENST00000269571.10	TSL:1 MANE Select	c.7C>T	p.Leu3Leu	synonymous	Exon 1 of 27	ENSP00000269571.4	P04626-1
	ERBB2	ENST00000584450.5	TSL:1	c.7C>T	p.Leu3Leu	synonymous	Exon 1 of 26	ENSP00000463714.1	J3QLU9
	ERBB2	ENST00000578199.5	TSL:1	c.-18+5064C>T		intron	N/A	ENSP00000462808.1	F5H1T4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000774 AC: 10 AN: 1292202 Hom.: 0 Cov.: 31 AF XY: 0.00000629 AC XY: 4 AN XY: 635854

African (AFR) AF: 0.00 AC: 0 AN: 26264

American (AMR) AF: 0.00 AC: 0 AN: 23340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22370

East Asian (EAS) AF: 0.00 AC: 0 AN: 28026

South Asian (SAS) AF: 0.00 AC: 0 AN: 67344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3786

European-Non Finnish (NFE) AF: 0.00000967 AC: 10 AN: 1034428

Other (OTH) AF: 0.00 AC: 0 AN: 53278

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.95
PhyloP100		0.28
PromoterAI		-0.070	Neutral

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: rs2058005545; hg19: chr17-37856498;