chr2-211679199-A-G

Variant names:

• chr2-211679199-A-G
• rs4673628
• NM_005235.3:c.1490-15T>C

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.1490-15T>C variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.437
• Publications: 24 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=-0.81).
• BP6: Variant 2-211679199-A-G is Benign according to our data. Variant chr2-211679199-A-G is described in ClinVar as Benign. ClinVar VariationId is 1210000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.1490-15T>C		intron_variant	Intron 12 of 27	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.1490-15T>C		intron_variant	Intron 12 of 27	1	NM_005235.3	ENSP00000342235.4
ERBB4	ENST00000436443.5	c.1490-15T>C		intron_variant	Intron 12 of 26	1		ENSP00000403204.1
ERBB4	ENST00000484594.5	n.1542-15T>C		intron_variant	Intron 12 of 19	1
ERBB4	ENST00000260943.11	c.1490-15T>C		intron_variant	Intron 12 of 26	5		ENSP00000260943.7

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

GnomAD2 exomes AF: 0.394 AC: 98688 AN: 250396 AF XY: 0.396

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 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

African (AFR) AF: 0.528 AC: 17653 AN: 33428

American (AMR) AF: 0.355 AC: 15833 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 12956 AN: 26092

East Asian (EAS) AF: 0.00593 AC: 235 AN: 39646

South Asian (SAS) AF: 0.371 AC: 31926 AN: 86154

European-Finnish (FIN) AF: 0.386 AC: 20557 AN: 53250

Middle Eastern (MID) AF: 0.542 AC: 3116 AN: 5752

European-Non Finnish (NFE) AF: 0.456 AC: 505854 AN: 1109592

Other (OTH) AF: 0.435 AC: 26211 AN: 60270

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

African (AFR) AF: 0.516 AC: 21335 AN: 41380

American (AMR) AF: 0.400 AC: 6114 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 1677 AN: 3468

East Asian (EAS) AF: 0.0128 AC: 66 AN: 5158

South Asian (SAS) AF: 0.353 AC: 1698 AN: 4816

European-Finnish (FIN) AF: 0.380 AC: 3992 AN: 10510

Middle Eastern (MID) AF: 0.527 AC: 154 AN: 292

European-Non Finnish (NFE) AF: 0.455 AC: 30907 AN: 67926

Other (OTH) AF: 0.462 AC: 973 AN: 2106

Alfa AF: 0.459 Hom.: 7290

Bravo AF: 0.447

Asia WGS AF: 0.196 AC: 686 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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 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. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Amyotrophic lateral sclerosis type 19 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.9
DANN	Benign	0.60
PhyloP100		0.44
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: rs4673628; hg19: chr2-212543924; COSMIC: COSV53526947;