2-212323745-C-T

Variant names:

• chr2-212323745-C-T
• rs905883
• NM_005235.3:c.83-198842G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005235.3(ERBB4):​c.83-198842G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.771 in 150,082 control chromosomes in the GnomAD database, including 47,188 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.77 (47188 hom., cov: 31)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.439
• Publications: 13 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.886 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005235.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	NM_005235.3	MANE Select	c.83-198842G>A		intron	N/A	NP_005226.1
	ERBB4	NM_001439005.1		c.83-198842G>A		intron	N/A	NP_001425934.1
	ERBB4	NM_001042599.2		c.83-198842G>A		intron	N/A	NP_001036064.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	ENST00000342788.9	TSL:1 MANE Select	c.83-198842G>A		intron	N/A	ENSP00000342235.4
	ERBB4	ENST00000436443.5	TSL:1	c.83-198842G>A		intron	N/A	ENSP00000403204.1
	ERBB4	ENST00000484594.5	TSL:1	n.135-198842G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.771 AC: 115605 AN: 149962 Hom.: 47186 Cov.: 31

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.976

Gnomad AMR AF: 0.793

Gnomad ASJ AF: 0.859

Gnomad EAS AF: 0.767

Gnomad SAS AF: 0.777

Gnomad FIN AF: 0.875

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.892

Gnomad OTH AF: 0.796

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.771 AC: 115649 AN: 150082 Hom.: 47188 Cov.: 31 AF XY: 0.770 AC XY: 56472 AN XY: 73294

African (AFR) AF: 0.524 AC: 21598 AN: 41196

American (AMR) AF: 0.792 AC: 11934 AN: 15062

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 2932 AN: 3414

East Asian (EAS) AF: 0.766 AC: 3916 AN: 5110

South Asian (SAS) AF: 0.777 AC: 3649 AN: 4698

European-Finnish (FIN) AF: 0.875 AC: 9064 AN: 10364

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.892 AC: 59762 AN: 66962

Other (OTH) AF: 0.798 AC: 1656 AN: 2076

Alfa AF: 0.854 Hom.: 22448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.66
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: rs905883; hg19: chr2-213188470;