rs17406681

Variant names:

• chr2-211538662-C-T
• rs17406681
• NM_005235.3:c.2487+23241G>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.2487+23241G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 151,700 control chromosomes in the GnomAD database, including 3,037 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 0.18 (3037 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.117
• 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: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.233 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	NM_005235.3	MANE Select	c.2487+23241G>A		intron	N/A	NP_005226.1	Q15303-1
	ERBB4	NM_001439005.1		c.2457+23241G>A		intron	N/A	NP_001425934.1
	ERBB4	NM_001042599.2		c.2487+23241G>A		intron	N/A	NP_001036064.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	ENST00000342788.9	TSL:1 MANE Select	c.2487+23241G>A		intron	N/A	ENSP00000342235.4	Q15303-1
	ERBB4	ENST00000436443.5	TSL:1	c.2487+23241G>A		intron	N/A	ENSP00000403204.1	Q15303-3
	ERBB4	ENST00000260943.11	TSL:5	c.2457+23241G>A		intron	N/A	ENSP00000260943.7	Q15303-4

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27341 AN: 151582 Hom.: 3030 Cov.: 32

Gnomad AFR AF: 0.0671

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0855

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.226

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

GnomAD4 genome AF: 0.180 AC: 27374 AN: 151700 Hom.: 3037 Cov.: 32 AF XY: 0.178 AC XY: 13160 AN XY: 74112

African (AFR) AF: 0.0674 AC: 2796 AN: 41476

American (AMR) AF: 0.234 AC: 3554 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 768 AN: 3458

East Asian (EAS) AF: 0.109 AC: 561 AN: 5152

South Asian (SAS) AF: 0.0869 AC: 419 AN: 4824

European-Finnish (FIN) AF: 0.240 AC: 2511 AN: 10484

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 16027 AN: 67776

Other (OTH) AF: 0.222 AC: 468 AN: 2106

Alfa AF: 0.220 Hom.: 15897

Bravo AF: 0.179

Asia WGS AF: 0.104 AC: 361 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.72
PhyloP100		0.12
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs17406681;

hg19: chr2-212403387;