chr2-201633304-T-C

Position:

• chr2-201633304-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001044385.3(TMEM237):​c.395+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,595,658 control chromosomes in the GnomAD database, including 168 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (79 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (89 hom.)
• Consequence: TMEM237 NM_001044385.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001297
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00500

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-201633304-T-C is Benign according to our data. Variant chr2-201633304-T-C is described in ClinVar as [Benign]. Clinvar id is 130593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201633304-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM237	NM_001044385.3	c.395+7A>G		splice_region_variant, intron_variant		ENST00000409883.7	NP_001037850.1
TMEM237	NM_152388.4	c.371+7A>G		splice_region_variant, intron_variant			NP_689601.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM237	ENST00000409883.7	c.395+7A>G		splice_region_variant, intron_variant		5	NM_001044385.3	ENSP00000386264.2

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2774 AN: 152134 Hom.: 79 Cov.: 32

Gnomad AFR AF: 0.0580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00701

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0382

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00809 AC: 1826 AN: 225756 Hom.: 49 AF XY: 0.00703 AC XY: 855 AN XY: 121538

Gnomad AFR exome AF: 0.0599

Gnomad AMR exome AF: 0.00305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0509

Gnomad SAS exome AF: 0.000672

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000207

Gnomad OTH exome AF: 0.00303

GnomAD4 exome AF: 0.00264 AC: 3808 AN: 1443406 Hom.: 89 Cov.: 30 AF XY: 0.00242 AC XY: 1734 AN XY: 716336

Gnomad4 AFR exome AF: 0.0547

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0326

Gnomad4 SAS exome AF: 0.000848

Gnomad4 FIN exome AF: 0.0000387

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.00591

GnomAD4 genome AF: 0.0183 AC: 2779 AN: 152252 Hom.: 79 Cov.: 32 AF XY: 0.0182 AC XY: 1356 AN XY: 74460

Gnomad4 AFR AF: 0.0581

Gnomad4 AMR AF: 0.00700

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0381

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00514 Hom.: 9

Bravo AF: 0.0216

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Joubert syndrome 14 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.7
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.052
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: rs78297522; hg19: chr2-202498027;