rs2289086

Variant names:

• chr2-211420378-T-C
• rs2289086
• NM_005235.3:c.3135+63A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005235.3(ERBB4):​c.3135+63A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,174,814 control chromosomes in the GnomAD database, including 87,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13431 hom., cov: 32)
  • Exomes 𝑓: 0.37 (74108 hom.)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.57
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-211420378-T-C is Benign according to our data. Variant chr2-211420378-T-C is described in ClinVar as Benign. ClinVar VariationId is 1283533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.3135+63A>G		intron_variant	Intron 25 of 27	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.3135+63A>G		intron_variant	Intron 25 of 27	1	NM_005235.3	ENSP00000342235.4
ERBB4	ENST00000436443.5	c.3135+63A>G		intron_variant	Intron 25 of 26	1		ENSP00000403204.1
ERBB4	ENST00000260943.11	c.3105+63A>G		intron_variant	Intron 25 of 26	5		ENSP00000260943.7

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61945 AN: 151702 Hom.: 13395 Cov.: 32

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.566

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.386

GnomAD4 exome AF: 0.373 AC: 381310 AN: 1022994 Hom.: 74108 AF XY: 0.379 AC XY: 198245 AN XY: 523538

African (AFR) AF: 0.547 AC: 13209 AN: 24140

American (AMR) AF: 0.422 AC: 16431 AN: 38896

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 7127 AN: 22956

East Asian (EAS) AF: 0.494 AC: 17165 AN: 34772

South Asian (SAS) AF: 0.561 AC: 41340 AN: 73684

European-Finnish (FIN) AF: 0.287 AC: 14242 AN: 49656

Middle Eastern (MID) AF: 0.393 AC: 1376 AN: 3500

European-Non Finnish (NFE) AF: 0.347 AC: 253602 AN: 730134

Other (OTH) AF: 0.372 AC: 16818 AN: 45256

GnomAD4 genome AF: 0.409 AC: 62045 AN: 151820 Hom.: 13431 Cov.: 32 AF XY: 0.409 AC XY: 30382 AN XY: 74230

African (AFR) AF: 0.542 AC: 22460 AN: 41448

American (AMR) AF: 0.399 AC: 6078 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1001 AN: 3466

East Asian (EAS) AF: 0.449 AC: 2310 AN: 5148

South Asian (SAS) AF: 0.567 AC: 2736 AN: 4824

European-Finnish (FIN) AF: 0.271 AC: 2866 AN: 10566

Middle Eastern (MID) AF: 0.390 AC: 114 AN: 292

European-Non Finnish (NFE) AF: 0.345 AC: 23402 AN: 67822

Other (OTH) AF: 0.387 AC: 816 AN: 2110

Alfa AF: 0.372 Hom.: 4528

Bravo AF: 0.421

Asia WGS AF: 0.513 AC: 1781 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 68% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 63. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.042
DANN	Benign	0.55
PhyloP100		-1.6
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: rs2289086; hg19: chr2-212285103;