rs397516980

Variant names:

• chr17-39724744-G-CTTT
• rs397516980
• NM_004448.4:c.2326delGinsCTTT

Your query was ambiguous. Multiple possible variants found:

• chr17-39724743-TG-TCTTT
• chr17-39724743-TG-TTTAT
• chr17-39724743-TG-TTTGT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PM5

The NM_004448.4(ERBB2):​c.2326delGinsCTTT​(p.Gly776delinsLeuCys) variant causes a missense, disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G776delinsCC) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ERBB2 NM_004448.4 missense, disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.91
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004448.4. Strenght limited to Supporting due to length of the change: 1aa.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-39724744-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13879.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_004448.4	c.2326delGinsCTTT	p.Gly776delinsLeuCys	missense_variant, disruptive_inframe_insertion	Exon 20 of 27	ENST00000269571.10	NP_004439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10	c.2326delGinsCTTT	p.Gly776delinsLeuCys	missense_variant, disruptive_inframe_insertion	Exon 20 of 27	1	NM_004448.4	ENSP00000269571.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397516980; hg19: chr17-37880997; COSMIC: COSV54077923;