chr2-211387469-A-T

Variant names:

• chr2-211387469-A-T
• rs1836721
• NM_005235.3:c.3184-319T>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.3184-319T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0811 in 152,258 control chromosomes in the GnomAD database, including 728 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 0.081 (728 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.641
• Publications: 4 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005235.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	NM_005235.3	MANE Select	c.3184-319T>A		intron	N/A	NP_005226.1
	ERBB4	NM_001439005.1		c.3154-319T>A		intron	N/A	NP_001425934.1
	ERBB4	NM_001042599.2		c.3136-319T>A		intron	N/A	NP_001036064.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	ENST00000342788.9	TSL:1 MANE Select	c.3184-319T>A		intron	N/A	ENSP00000342235.4
	ERBB4	ENST00000436443.5	TSL:1	c.3136-319T>A		intron	N/A	ENSP00000403204.1
	ERBB4	ENST00000260943.11	TSL:5	c.3106-319T>A		intron	N/A	ENSP00000260943.7

Frequencies

GnomAD3 genomes AF: 0.0812 AC: 12356 AN: 152140 Hom.: 729 Cov.: 32

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.0907

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.0758

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.0946

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

GnomAD4 genome AF: 0.0811 AC: 12345 AN: 152258 Hom.: 728 Cov.: 32 AF XY: 0.0778 AC XY: 5793 AN XY: 74434

African (AFR) AF: 0.0199 AC: 827 AN: 41566

American (AMR) AF: 0.0905 AC: 1385 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 548 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.0255 AC: 123 AN: 4826

European-Finnish (FIN) AF: 0.0758 AC: 804 AN: 10602

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8258 AN: 68010

Other (OTH) AF: 0.0937 AC: 198 AN: 2114

Alfa AF: 0.0957 Hom.: 118

Bravo AF: 0.0820

Asia WGS AF: 0.0140 AC: 51 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		0.64
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: rs1836721; hg19: chr2-212252194;