chr2-211422209-A-T

Variant names:

• chr2-211422209-A-T
• rs3791709
• NM_005235.3:c.2867-105T>A

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.2867-105T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 737,032 control chromosomes in the GnomAD database, including 36,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5359 hom., cov: 32)
  • Exomes 𝑓: 0.31 (31222 hom.)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.608
• Publications: 8 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 2-211422209-A-T is Benign according to our data. Variant chr2-211422209-A-T is described in ClinVar as Benign. ClinVar VariationId is 1278598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.2867-105T>A		intron_variant	Intron 23 of 27	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.2867-105T>A		intron_variant	Intron 23 of 27	1	NM_005235.3	ENSP00000342235.4
ERBB4	ENST00000436443.5	c.2867-105T>A		intron_variant	Intron 23 of 26	1		ENSP00000403204.1
ERBB4	ENST00000260943.11	c.2837-105T>A		intron_variant	Intron 23 of 26	5		ENSP00000260943.7

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37834 AN: 151704 Hom.: 5350 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.528

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.253

GnomAD4 exome AF: 0.310 AC: 181548 AN: 585210 Hom.: 31222 AF XY: 0.324 AC XY: 102800 AN XY: 317524

African (AFR) AF: 0.122 AC: 1926 AN: 15734

American (AMR) AF: 0.305 AC: 11036 AN: 36158

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 5011 AN: 19122

East Asian (EAS) AF: 0.417 AC: 12879 AN: 30912

South Asian (SAS) AF: 0.526 AC: 34166 AN: 64984

European-Finnish (FIN) AF: 0.271 AC: 9946 AN: 36690

Middle Eastern (MID) AF: 0.347 AC: 1350 AN: 3894

European-Non Finnish (NFE) AF: 0.278 AC: 96589 AN: 347408

Other (OTH) AF: 0.285 AC: 8645 AN: 30308

GnomAD4 genome AF: 0.249 AC: 37861 AN: 151822 Hom.: 5359 Cov.: 32 AF XY: 0.255 AC XY: 18896 AN XY: 74204

African (AFR) AF: 0.129 AC: 5371 AN: 41518

American (AMR) AF: 0.286 AC: 4359 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 840 AN: 3462

East Asian (EAS) AF: 0.358 AC: 1845 AN: 5148

South Asian (SAS) AF: 0.529 AC: 2542 AN: 4804

European-Finnish (FIN) AF: 0.263 AC: 2783 AN: 10576

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.285 AC: 19330 AN: 67772

Other (OTH) AF: 0.256 AC: 540 AN: 2112

Alfa AF: 0.257 Hom.: 623

Bravo AF: 0.238

Asia WGS AF: 0.436 AC: 1512 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 31, 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 28% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 26. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.6
DANN	Benign	0.59
PhyloP100		-0.61
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: rs3791709; hg19: chr2-212286934;