2-211994793-G-A

Variant names:

• chr2-211994793-G-A
• rs10175279
• NM_005235.3:c.235-47177C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005235.3(ERBB4):​c.235-47177C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 152,044 control chromosomes in the GnomAD database, including 11,633 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 0.36 (11633 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.791
• Publications: 4 publications found

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]

ERBB4 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 19

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.235-47177C>T		intron_variant	Intron 2 of 27	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.235-47177C>T		intron_variant	Intron 2 of 27	1	NM_005235.3	ENSP00000342235.4

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54584 AN: 151926 Hom.: 11640 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.626

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.0329

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.499

Gnomad OTH AF: 0.355

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

GnomAD4 genome AF: 0.359 AC: 54564 AN: 152044 Hom.: 11633 Cov.: 32 AF XY: 0.350 AC XY: 25993 AN XY: 74294

African (AFR) AF: 0.180 AC: 7449 AN: 41492

American (AMR) AF: 0.308 AC: 4705 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1426 AN: 3468

East Asian (EAS) AF: 0.0328 AC: 170 AN: 5182

South Asian (SAS) AF: 0.275 AC: 1324 AN: 4822

European-Finnish (FIN) AF: 0.398 AC: 4199 AN: 10548

Middle Eastern (MID) AF: 0.377 AC: 110 AN: 292

European-Non Finnish (NFE) AF: 0.499 AC: 33874 AN: 67936

Other (OTH) AF: 0.349 AC: 736 AN: 2106

Alfa AF: 0.365 Hom.: 7350

Bravo AF: 0.345

Asia WGS AF: 0.138 AC: 483 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.3
DANN	Benign	0.60
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs10175279; hg19: chr2-212859518; COSMIC: COSV53547460;