chr2-211947372-T-C

Variant names:

• chr2-211947372-T-C
• rs839541
• NM_005235.3:c.421+58A>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.421+58A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,355,306 control chromosomes in the GnomAD database, including 50,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6717 hom., cov: 32)
  • Exomes 𝑓: 0.26 (43508 hom.)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.40
• Publications: 19 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=-0.94).
• BP6: Variant 2-211947372-T-C is Benign according to our data. Variant chr2-211947372-T-C is described in ClinVar as Benign. ClinVar VariationId is 1273302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.421+58A>G		intron_variant	Intron 3 of 27	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.421+58A>G		intron_variant	Intron 3 of 27	1	NM_005235.3	ENSP00000342235.4

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43821 AN: 152016 Hom.: 6697 Cov.: 32

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.393

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.306

GnomAD4 exome AF: 0.259 AC: 311854 AN: 1203172 Hom.: 43508 AF XY: 0.263 AC XY: 160791 AN XY: 611370

African (AFR) AF: 0.359 AC: 10209 AN: 28466

American (AMR) AF: 0.405 AC: 17683 AN: 43662

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 8582 AN: 24442

East Asian (EAS) AF: 0.394 AC: 15106 AN: 38342

South Asian (SAS) AF: 0.414 AC: 33175 AN: 80138

European-Finnish (FIN) AF: 0.220 AC: 11482 AN: 52258

Middle Eastern (MID) AF: 0.332 AC: 1627 AN: 4906

European-Non Finnish (NFE) AF: 0.227 AC: 200015 AN: 879254

Other (OTH) AF: 0.270 AC: 13975 AN: 51704

GnomAD4 genome AF: 0.288 AC: 43878 AN: 152134 Hom.: 6717 Cov.: 32 AF XY: 0.292 AC XY: 21754 AN XY: 74376

African (AFR) AF: 0.351 AC: 14541 AN: 41476

American (AMR) AF: 0.350 AC: 5339 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 1313 AN: 3470

East Asian (EAS) AF: 0.393 AC: 2036 AN: 5182

South Asian (SAS) AF: 0.407 AC: 1966 AN: 4830

European-Finnish (FIN) AF: 0.220 AC: 2329 AN: 10576

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15428 AN: 68014

Other (OTH) AF: 0.304 AC: 643 AN: 2112

Alfa AF: 0.256 Hom.: 651

Bravo AF: 0.301

Asia WGS AF: 0.392 AC: 1363 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 38% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 35. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.049
DANN	Benign	0.51
PhyloP100		-3.4
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: rs839541; hg19: chr2-212812097; COSMIC: COSV53500717;