2-212343532-G-T

Variant names:

• chr2-212343532-G-T
• rs6754674
• NM_005235.3:c.82+194917C>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+194917C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 151,858 control chromosomes in the GnomAD database, including 18,702 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 0.47 (18702 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0850
• Publications: 2 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.82+194917C>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+194917C>A		intron_variant	Intron 1 of 27	1	NM_005235.3	ENSP00000342235.4

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71690 AN: 151740 Hom.: 18692 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.636

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.536

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

GnomAD4 genome AF: 0.472 AC: 71719 AN: 151858 Hom.: 18702 Cov.: 32 AF XY: 0.473 AC XY: 35065 AN XY: 74188

African (AFR) AF: 0.250 AC: 10340 AN: 41398

American (AMR) AF: 0.635 AC: 9692 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 2157 AN: 3472

East Asian (EAS) AF: 0.789 AC: 4063 AN: 5150

South Asian (SAS) AF: 0.484 AC: 2333 AN: 4820

European-Finnish (FIN) AF: 0.465 AC: 4902 AN: 10536

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36374 AN: 67916

Other (OTH) AF: 0.539 AC: 1137 AN: 2108

Alfa AF: 0.461 Hom.: 2529

Bravo AF: 0.479

Asia WGS AF: 0.636 AC: 2208 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.34
DANN	Benign	0.38
PhyloP100		-0.085
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: rs6754674; hg19: chr2-213208256;