rs13393577

Variant names:

• chr2-212432139-T-C
• rs13393577
• NM_005235.3:c.82+106310A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005235.3(ERBB4):​c.82+106310A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 152,228 control chromosomes in the GnomAD database, including 868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.10 (868 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.15
• Publications: 36 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-212432139-T-C is Benign according to our data. Variant chr2-212432139-T-C is described in ClinVar as Benign. ClinVar VariationId is 1598694.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.128 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.82+106310A>G		intron	N/A	NP_005226.1	Q15303-1
	ERBB4	NM_001439005.1		c.82+106310A>G		intron	N/A	NP_001425934.1
	ERBB4	NM_001042599.2		c.82+106310A>G		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.82+106310A>G		intron	N/A	ENSP00000342235.4	Q15303-1
	ERBB4	ENST00000436443.5	TSL:1	c.82+106310A>G		intron	N/A	ENSP00000403204.1	Q15303-3
	ERBB4	ENST00000484594.5	TSL:1	n.134+106310A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15723 AN: 152110 Hom.: 861 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0967

Gnomad ASJ AF: 0.0568

Gnomad EAS AF: 0.0491

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0906

Gnomad OTH AF: 0.0946

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

GnomAD4 genome AF: 0.103 AC: 15755 AN: 152228 Hom.: 868 Cov.: 32 AF XY: 0.104 AC XY: 7750 AN XY: 74434

African (AFR) AF: 0.130 AC: 5421 AN: 41556

American (AMR) AF: 0.0970 AC: 1483 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 197 AN: 3468

East Asian (EAS) AF: 0.0492 AC: 255 AN: 5186

South Asian (SAS) AF: 0.136 AC: 659 AN: 4832

European-Finnish (FIN) AF: 0.127 AC: 1347 AN: 10594

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0906 AC: 6157 AN: 67986

Other (OTH) AF: 0.0936 AC: 198 AN: 2116

Alfa AF: 0.0928 Hom.: 2192

Bravo AF: 0.103

Asia WGS AF: 0.115 AC: 400 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	14
DANN	Benign	0.60
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs13393577; hg19: chr2-213296863; COSMIC: COSV53504887;