2-211380227-G-A

Variant names:

• chr2-211380227-G-A
• rs1836724
• NM_005235.3:c.*3388C>T

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.*3388C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 231,818 control chromosomes in the GnomAD database, including 43,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26277 hom., cov: 31)
  • Exomes 𝑓: 0.64 (16742 hom.)
• Consequence: ERBB4 NM_005235.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.409
• Publications: 25 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=-0.92).
• BP6: Variant 2-211380227-G-A is Benign according to our data. Variant chr2-211380227-G-A is described in ClinVar as [Benign]. Clinvar id is 1230173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.*3388C>T		3_prime_UTR_variant	Exon 28 of 28	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.*3388C>T		3_prime_UTR_variant	Exon 28 of 28	1	NM_005235.3	ENSP00000342235.4
ERBB4	ENST00000436443.5	c.*3388C>T		3_prime_UTR_variant	Exon 27 of 27	1		ENSP00000403204.1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87672 AN: 151656 Hom.: 26267 Cov.: 31

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.603

Gnomad ASJ AF: 0.626

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.768

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.602

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.560

GnomAD4 exome AF: 0.642 AC: 51368 AN: 80044 Hom.: 16742 Cov.: 0 AF XY: 0.647 AC XY: 23814 AN XY: 36792

African (AFR) AF: 0.414 AC: 1592 AN: 3842

American (AMR) AF: 0.606 AC: 1506 AN: 2484

Ashkenazi Jewish (ASJ) AF: 0.631 AC: 3188 AN: 5056

East Asian (EAS) AF: 0.772 AC: 8700 AN: 11272

South Asian (SAS) AF: 0.741 AC: 514 AN: 694

European-Finnish (FIN) AF: 0.672 AC: 39 AN: 58

Middle Eastern (MID) AF: 0.643 AC: 310 AN: 482

European-Non Finnish (NFE) AF: 0.636 AC: 31431 AN: 49448

Other (OTH) AF: 0.609 AC: 4088 AN: 6708

GnomAD4 genome AF: 0.578 AC: 87710 AN: 151774 Hom.: 26277 Cov.: 31 AF XY: 0.582 AC XY: 43137 AN XY: 74174

African (AFR) AF: 0.414 AC: 17157 AN: 41404

American (AMR) AF: 0.604 AC: 9175 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 2168 AN: 3466

East Asian (EAS) AF: 0.753 AC: 3880 AN: 5150

South Asian (SAS) AF: 0.768 AC: 3709 AN: 4830

European-Finnish (FIN) AF: 0.625 AC: 6593 AN: 10554

Middle Eastern (MID) AF: 0.613 AC: 179 AN: 292

European-Non Finnish (NFE) AF: 0.636 AC: 43164 AN: 67860

Other (OTH) AF: 0.559 AC: 1178 AN: 2108

Alfa AF: 0.614 Hom.: 88409

Bravo AF: 0.565

Asia WGS AF: 0.688 AC: 2390 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 24, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29125883) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.44
DANN	Benign	0.37
PhyloP100		-0.41
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: rs1836724; hg19: chr2-212244952;