2-211485520-T-C

Position:

• chr2-211485520-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005235.3(ERBB4):​c.2488-54420A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 151,972 control chromosomes in the GnomAD database, including 4,347 homozygotes. 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: 𝑓 0.23 (4347 hom., cov: 30)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03

Genes affected

ERBB4 (HGNC:3432): (erb-b2 receptor tyrosine kinase 4) This gene is a member of the Tyr protein kinase family and the epidermal growth factor receptor subfamily. It encodes a single-pass type I membrane protein with multiple cysteine rich domains, a transmembrane domain, a tyrosine kinase domain, a phosphotidylinositol-3 kinase binding site and a PDZ domain binding motif. The protein binds to and is activated by neuregulins and other factors and induces a variety of cellular responses including mitogenesis and differentiation. Multiple proteolytic events allow for the release of a cytoplasmic fragment and an extracellular fragment. Mutations in this gene have been associated with cancer. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB4	NM_005235.3	c.2488-54420A>G		intron_variant		ENST00000342788.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB4	ENST00000342788.9	c.2488-54420A>G		intron_variant		1	NM_005235.3	P4
ERBB4	ENST00000436443.5	c.2488-54420A>G		intron_variant		1		A1
ERBB4	ENST00000260943.11	c.2458-54420A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34824 AN: 151854 Hom.: 4333 Cov.: 30

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.222

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.230 AC: 34880 AN: 151972 Hom.: 4347 Cov.: 30 AF XY: 0.231 AC XY: 17145 AN XY: 74274

Gnomad4 AFR AF: 0.325

Gnomad4 AMR AF: 0.232

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.298

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.197

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.219

Alfa AF: 0.172 Hom.: 1295

Bravo AF: 0.236

Asia WGS AF: 0.218 AC: 757 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.22
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs13021324; hg19: chr2-212350245;