2-212031846-A-G

Variant names:

• chr2-212031846-A-G
• rs7607942
• NM_005235.3:c.235-84230T>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.235-84230T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 151,974 control chromosomes in the GnomAD database, including 5,360 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 0.24 (5360 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41
• Publications: 11 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=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.235-84230T>C		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.235-84230T>C		intron_variant	Intron 2 of 27	1	NM_005235.3	ENSP00000342235.4

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35803 AN: 151856 Hom.: 5361 Cov.: 32

Gnomad AFR AF: 0.0799

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.0322

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.224

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

GnomAD4 genome AF: 0.235 AC: 35785 AN: 151974 Hom.: 5360 Cov.: 32 AF XY: 0.232 AC XY: 17223 AN XY: 74280

African (AFR) AF: 0.0796 AC: 3306 AN: 41524

American (AMR) AF: 0.185 AC: 2813 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 963 AN: 3464

East Asian (EAS) AF: 0.0323 AC: 167 AN: 5172

South Asian (SAS) AF: 0.183 AC: 884 AN: 4818

European-Finnish (FIN) AF: 0.338 AC: 3563 AN: 10546

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.340 AC: 23101 AN: 67904

Other (OTH) AF: 0.220 AC: 465 AN: 2110

Alfa AF: 0.284 Hom.: 3467

Bravo AF: 0.218

Asia WGS AF: 0.0830 AC: 292 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.72
PhyloP100		2.4
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: rs7607942; hg19: chr2-212896571;