2-212276574-A-T

Variant names:

• chr2-212276574-A-T
• rs16848144
• NM_005235.3:c.83-151671T>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.83-151671T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0754 in 151,848 control chromosomes in the GnomAD database, including 581 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 0.075 (581 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.83-151671T>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.83-151671T>A		intron_variant	Intron 1 of 27	1	NM_005235.3	ENSP00000342235.4

Frequencies

GnomAD3 genomes AF: 0.0753 AC: 11425 AN: 151730 Hom.: 578 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0557

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.00330

Gnomad SAS AF: 0.0913

Gnomad FIN AF: 0.0622

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0519

Gnomad OTH AF: 0.0790

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

GnomAD4 genome AF: 0.0754 AC: 11454 AN: 151848 Hom.: 581 Cov.: 32 AF XY: 0.0752 AC XY: 5578 AN XY: 74220

African (AFR) AF: 0.136 AC: 5650 AN: 41464

American (AMR) AF: 0.0557 AC: 846 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3468

East Asian (EAS) AF: 0.00331 AC: 17 AN: 5140

South Asian (SAS) AF: 0.0912 AC: 440 AN: 4824

European-Finnish (FIN) AF: 0.0622 AC: 661 AN: 10620

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0520 AC: 3523 AN: 67814

Other (OTH) AF: 0.0782 AC: 165 AN: 2110

Alfa AF: 0.0645 Hom.: 55

Bravo AF: 0.0765

Asia WGS AF: 0.0430 AC: 152 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.6
DANN	Benign	0.48
PhyloP100		1.4
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: rs16848144; hg19: chr2-213141299;