chr2-211679199-A-G

Position:

• chr2-211679199-A-G

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.1490-15T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,610,666 control chromosomes in the GnomAD database, including 158,880 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15671 hom., cov: 30)
  • Exomes 𝑓: 0.43 (143209 hom.)
• Consequence: ERBB4 NM_005235.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.437

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=-0.81).
• BP6: Variant 2-211679199-A-G is Benign according to our data. Variant chr2-211679199-A-G is described in ClinVar as [Benign]. Clinvar id is 1210000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-211679199-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB4	NM_005235.3	c.1490-15T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000342788.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB4	ENST00000342788.9	c.1490-15T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005235.3	P4
ERBB4	ENST00000436443.5	c.1490-15T>C		splice_polypyrimidine_tract_variant, intron_variant		1		A1
ERBB4	ENST00000484594.5	n.1542-15T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
ERBB4	ENST00000260943.11	c.1490-15T>C		splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67322 AN: 151722 Hom.: 15666 Cov.: 30

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.484

Gnomad EAS AF: 0.0128

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.526

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.463

GnomAD3 exomes AF: 0.394 AC: 98688 AN: 250396 Hom.: 21267 AF XY: 0.396 AC XY: 53573 AN XY: 135364

Gnomad AFR exome AF: 0.521

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.495

Gnomad EAS exome AF: 0.0131

Gnomad SAS exome AF: 0.366

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.450

Gnomad OTH exome AF: 0.427

GnomAD4 exome AF: 0.435 AC: 634341 AN: 1458824 Hom.: 143209 Cov.: 35 AF XY: 0.433 AC XY: 314308 AN XY: 725774

Gnomad4 AFR exome AF: 0.528

Gnomad4 AMR exome AF: 0.355

Gnomad4 ASJ exome AF: 0.497

Gnomad4 EAS exome AF: 0.00593

Gnomad4 SAS exome AF: 0.371

Gnomad4 FIN exome AF: 0.386

Gnomad4 NFE exome AF: 0.456

Gnomad4 OTH exome AF: 0.435

GnomAD4 genome AF: 0.444 AC: 67370 AN: 151842 Hom.: 15671 Cov.: 30 AF XY: 0.436 AC XY: 32324 AN XY: 74216

Gnomad4 AFR AF: 0.516

Gnomad4 AMR AF: 0.400

Gnomad4 ASJ AF: 0.484

Gnomad4 EAS AF: 0.0128

Gnomad4 SAS AF: 0.353

Gnomad4 FIN AF: 0.380

Gnomad4 NFE AF: 0.455

Gnomad4 OTH AF: 0.462

Alfa AF: 0.463 Hom.: 5155

Bravo AF: 0.447

Asia WGS AF: 0.196 AC: 686 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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 53% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 49. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Amyotrophic lateral sclerosis type 19 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.9
DANN	Benign	0.60

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: rs4673628; hg19: chr2-212543924; COSMIC: COSV53526947;