2-212124685-G-C

Variant names:

• chr2-212124685-G-C
• rs6723461
• NM_005235.3:c.234+67C>G

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.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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0560
• Publications: 4 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=-0.83).
• 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.234+67C>G		intron_variant	Intron 2 of 27	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.234+67C>G		intron_variant	Intron 2 of 27	1	NM_005235.3	ENSP00000342235.4

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

African (AFR) AF: 0.169 AC: 5459 AN: 32272

American (AMR) AF: 0.0271 AC: 1210 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 1666 AN: 25774

East Asian (EAS) AF: 0.000304 AC: 12 AN: 39422

South Asian (SAS) AF: 0.0392 AC: 3326 AN: 84906

European-Finnish (FIN) AF: 0.0258 AC: 1376 AN: 53272

Middle Eastern (MID) AF: 0.0571 AC: 314 AN: 5500

European-Non Finnish (NFE) AF: 0.0367 AC: 38900 AN: 1060814

Other (OTH) AF: 0.0455 AC: 2660 AN: 58472

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

African (AFR) AF: 0.168 AC: 6953 AN: 41480

American (AMR) AF: 0.0421 AC: 644 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0692 AC: 240 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0331 AC: 160 AN: 4828

European-Finnish (FIN) AF: 0.0299 AC: 317 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0348 AC: 2367 AN: 68008

Other (OTH) AF: 0.0673 AC: 142 AN: 2110

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: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

- -

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.42
PhyloP100		-0.056
PromoterAI		0.018	Neutral
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: rs6723461; hg19: chr2-212989410;