rs2289086

Positions:

• chr2-211420378-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
ERBB4	NM_005235.3	c.3135+63A>G		intron_variant		ENST00000342788.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB4	ENST00000342788.9	c.3135+63A>G		intron_variant		1	NM_005235.3	P4
ERBB4	ENST00000436443.5	c.3135+63A>G		intron_variant		1		A1
ERBB4	ENST00000260943.11	c.3105+63A>G		intron_variant		5

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

Gnomad4 AFR exome AF: 0.547

Gnomad4 AMR exome AF: 0.422

Gnomad4 ASJ exome AF: 0.310

Gnomad4 EAS exome AF: 0.494

Gnomad4 SAS exome AF: 0.561

Gnomad4 FIN exome AF: 0.287

Gnomad4 NFE exome AF: 0.347

Gnomad4 OTH exome AF: 0.372

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

Gnomad4 AFR AF: 0.542

Gnomad4 AMR AF: 0.399

Gnomad4 ASJ AF: 0.289

Gnomad4 EAS AF: 0.449

Gnomad4 SAS AF: 0.567

Gnomad4 FIN AF: 0.271

Gnomad4 NFE AF: 0.345

Gnomad4 OTH AF: 0.387

Alfa AF: 0.372 Hom.: 3030

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2289086; hg19: chr2-212285103;