rs267599192

Variant names:

• chr2-211673250-G-A
• rs267599192
• NM_005235.3:c.1630C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005235.3(ERBB4):​c.1630C>T​(p.Arg544Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ERBB4 NM_005235.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.20
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	NM_005235.3	MANE Select	c.1630C>T	p.Arg544Trp	missense	Exon 14 of 28	NP_005226.1
	ERBB4	NM_001439005.1		c.1630C>T	p.Arg544Trp	missense	Exon 14 of 28	NP_001425934.1
	ERBB4	NM_001042599.2		c.1630C>T	p.Arg544Trp	missense	Exon 14 of 27	NP_001036064.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	ENST00000342788.9	TSL:1 MANE Select	c.1630C>T	p.Arg544Trp	missense	Exon 14 of 28	ENSP00000342235.4
	ERBB4	ENST00000436443.5	TSL:1	c.1630C>T	p.Arg544Trp	missense	Exon 14 of 27	ENSP00000403204.1
	ERBB4	ENST00000484594.5	TSL:1	n.1682C>T		non_coding_transcript_exon	Exon 14 of 20

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460606 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726710

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110932

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.54		Loss of disorder (P = 0.0022)
MVP		0.72
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.91
Mutation Taster		=62/38	disease causing (ClinVar)

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: rs267599192; hg19: chr2-212537975; COSMIC: COSV53516478;