2-201627272-G-T

Variant names:

• chr2-201627272-G-T
• rs2540450
• NM_001044385.3:c.1037+49C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001044385.3(TMEM237):​c.1037+49C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000855 in 1,169,592 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: TMEM237 NM_001044385.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.472
• Publications: 0 publications found

Genes affected

TMEM237 (HGNC:14432): (transmembrane protein 237) The protein encoded by this gene is a tetraspanin protein that is thought to be involved in WNT signaling. Defects in this gene are a cause of Joubert syndrome-14. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

TMEM237 Gene-Disease associations (from GenCC):

• Joubert syndrome 14

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with renal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM237	NM_001044385.3	c.1037+49C>A		intron_variant	Intron 11 of 12	ENST00000409883.7	NP_001037850.1
TMEM237	NM_152388.4	c.1013+49C>A		intron_variant	Intron 11 of 12		NP_689601.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM237	ENST00000409883.7	c.1037+49C>A		intron_variant	Intron 11 of 12	5	NM_001044385.3	ENSP00000386264.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.55e-7 AC: 1 AN: 1169592 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 588104

African (AFR) AF: 0.00 AC: 0 AN: 27190

American (AMR) AF: 0.00 AC: 0 AN: 33556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23176

East Asian (EAS) AF: 0.00 AC: 0 AN: 36346

South Asian (SAS) AF: 0.00 AC: 0 AN: 73180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5184

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 870280

Other (OTH) AF: 0.0000198 AC: 1 AN: 50584

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.6
DANN	Benign	0.63
PhyloP100		0.47

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: rs2540450; hg19: chr2-202491995;