2-211486942-T-G

Variant names:

• chr2-211486942-T-G
• rs9941626
• NM_005235.3:c.2488-55842A>C

Variant summary

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

The NM_005235.3(ERBB4):​c.2488-55842A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 151,790 control chromosomes in the GnomAD database, including 6,443 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 0.27 (6443 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.46
• Publications: 6 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.2488-55842A>C		intron_variant	Intron 20 of 27	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.2488-55842A>C		intron_variant	Intron 20 of 27	1	NM_005235.3	ENSP00000342235.4
ERBB4	ENST00000436443.5	c.2488-55842A>C		intron_variant	Intron 20 of 26	1		ENSP00000403204.1
ERBB4	ENST00000260943.11	c.2458-55842A>C		intron_variant	Intron 20 of 26	5		ENSP00000260943.7

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40423 AN: 151676 Hom.: 6420 Cov.: 32

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.251

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

GnomAD4 genome AF: 0.267 AC: 40489 AN: 151790 Hom.: 6443 Cov.: 32 AF XY: 0.267 AC XY: 19812 AN XY: 74188

African (AFR) AF: 0.450 AC: 18578 AN: 41276

American (AMR) AF: 0.251 AC: 3823 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 554 AN: 3468

East Asian (EAS) AF: 0.298 AC: 1545 AN: 5176

South Asian (SAS) AF: 0.152 AC: 734 AN: 4820

European-Finnish (FIN) AF: 0.200 AC: 2100 AN: 10502

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.183 AC: 12460 AN: 67984

Other (OTH) AF: 0.248 AC: 524 AN: 2112

Alfa AF: 0.172 Hom.: 1174

Bravo AF: 0.278

Asia WGS AF: 0.225 AC: 779 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.10
DANN	Benign	0.61
PhyloP100		-1.5
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: rs9941626; hg19: chr2-212351667;