chr2-212522665-C-T

Variant names:

• chr2-212522665-C-T
• rs1026882
• NM_005235.3:c.82+15784G>A

Variant summary

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

The NM_005235.3(ERBB4):​c.82+15784G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 151,768 control chromosomes in the GnomAD database, including 29,752 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 0.60 (29752 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0100
• Publications: 14 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.82+15784G>A		intron_variant	Intron 1 of 27	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.82+15784G>A		intron_variant	Intron 1 of 27	1	NM_005235.3	ENSP00000342235.4
ERBB4	ENST00000436443.5	c.82+15784G>A		intron_variant	Intron 1 of 26	1		ENSP00000403204.1
ERBB4	ENST00000484594.5	n.134+15784G>A		intron_variant	Intron 1 of 19	1
ERBB4	ENST00000260943.11	c.82+15784G>A		intron_variant	Intron 1 of 26	5		ENSP00000260943.7

Frequencies

GnomAD3 genomes AF: 0.604 AC: 91631 AN: 151650 Hom.: 29686 Cov.: 32

Gnomad AFR AF: 0.839

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.562

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

GnomAD4 genome AF: 0.605 AC: 91758 AN: 151768 Hom.: 29752 Cov.: 32 AF XY: 0.598 AC XY: 44328 AN XY: 74176

African (AFR) AF: 0.839 AC: 34812 AN: 41480

American (AMR) AF: 0.473 AC: 7172 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 1761 AN: 3464

East Asian (EAS) AF: 0.111 AC: 573 AN: 5162

South Asian (SAS) AF: 0.491 AC: 2361 AN: 4808

European-Finnish (FIN) AF: 0.557 AC: 5890 AN: 10570

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.553 AC: 37461 AN: 67802

Other (OTH) AF: 0.556 AC: 1168 AN: 2102

Alfa AF: 0.563 Hom.: 40371

Bravo AF: 0.609

Asia WGS AF: 0.330 AC: 1151 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.2
DANN	Benign	0.68
PhyloP100		0.010
Mutation Taster		=100/0	polymorphism (auto)

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: rs1026882; hg19: chr2-213387389; COSMIC: COSV53543685;