rs6723461

chr2-212124685-G-Cchr2-212124685-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005235.3(ERBB4):c.234+67C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 1,557,234 control chromosomes in the GnomAD database, including 2,215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.071 (681 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1534 hom.)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0560

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-212124685-G-C is Benign according to our data. Variant chr2-212124685-G-C is described in ClinVar as [Benign]. Clinvar id is 1239508.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB4	NM_005235.3	c.234+67C>G		intron_variant		ENST00000342788.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB4	ENST00000342788.9	c.234+67C>G		intron_variant		1	NM_005235.3	P4

Frequencies

GnomAD3 genomes AF: 0.0712 AC: 10826 AN: 152074 Hom.: 681 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0422

Gnomad ASJ AF: 0.0692

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0331

Gnomad FIN AF: 0.0299

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0348

Gnomad OTH AF: 0.0675

GnomAD4 exome AF: 0.0391 AC: 54923 AN: 1405042 Hom.: 1534 Cov.: 23 AF XY: 0.0385 AC XY: 27064 AN XY: 702166

Gnomad4 AFR exome AF: 0.169

Gnomad4 AMR exome AF: 0.0271

Gnomad4 ASJ exome AF: 0.0646

Gnomad4 EAS exome AF: 0.000304

Gnomad4 SAS exome AF: 0.0392

Gnomad4 FIN exome AF: 0.0258

Gnomad4 NFE exome AF: 0.0367

Gnomad4 OTH exome AF: 0.0455

GnomAD4 genome AF: 0.0712 AC: 10841 AN: 152192 Hom.: 681 Cov.: 32 AF XY: 0.0697 AC XY: 5188 AN XY: 74432

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.0421

Gnomad4 ASJ AF: 0.0692

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0331

Gnomad4 FIN AF: 0.0299

Gnomad4 NFE AF: 0.0348

Gnomad4 OTH AF: 0.0673

Alfa AF: 0.0159 Hom.: 12

Bravo AF: 0.0771

Asia WGS AF: 0.0250 AC: 87 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.5
Dann	Benign	0.42

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: rs6723461; hg19: chr2-212989410; COSMIC: COSV104593812;