rs2540450

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-201627272-G-A
• chr2-201627272-G-C
• chr2-201627272-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001044385.3(TMEM237):​c.1037+49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 1,319,112 control chromosomes in the GnomAD database, including 69,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7025 hom., cov: 32)
  • Exomes 𝑓: 0.32 (62603 hom.)
• Consequence: TMEM237 NM_001044385.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.472
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-201627272-G-A is Benign according to our data. Variant chr2-201627272-G-A is described in ClinVar as Benign. ClinVar VariationId is 257314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM237	NM_001044385.3	c.1037+49C>T		intron_variant	Intron 11 of 12	ENST00000409883.7	NP_001037850.1
TMEM237	NM_152388.4	c.1013+49C>T		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>T		intron_variant	Intron 11 of 12	5	NM_001044385.3	ENSP00000386264.2

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43981 AN: 151928 Hom.: 7023 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.295

GnomAD2 exomes AF: 0.343 AC: 59191 AN: 172780 AF XY: 0.339

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.417

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.623

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.294

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.319 AC: 372568 AN: 1167066 Hom.: 62603 Cov.: 15 AF XY: 0.320 AC XY: 187532 AN XY: 586834

African (AFR) AF: 0.178 AC: 4833 AN: 27150

American (AMR) AF: 0.410 AC: 13750 AN: 33498

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 7132 AN: 23146

East Asian (EAS) AF: 0.627 AC: 22779 AN: 36304

South Asian (SAS) AF: 0.341 AC: 24898 AN: 73036

European-Finnish (FIN) AF: 0.358 AC: 17894 AN: 50038

Middle Eastern (MID) AF: 0.292 AC: 1515 AN: 5182

European-Non Finnish (NFE) AF: 0.304 AC: 263530 AN: 868228

Other (OTH) AF: 0.322 AC: 16237 AN: 50484

GnomAD4 genome AF: 0.289 AC: 44002 AN: 152046 Hom.: 7025 Cov.: 32 AF XY: 0.297 AC XY: 22085 AN XY: 74320

African (AFR) AF: 0.184 AC: 7653 AN: 41488

American (AMR) AF: 0.354 AC: 5414 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1079 AN: 3464

East Asian (EAS) AF: 0.628 AC: 3242 AN: 5166

South Asian (SAS) AF: 0.342 AC: 1644 AN: 4812

European-Finnish (FIN) AF: 0.383 AC: 4045 AN: 10552

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.294 AC: 20001 AN: 67972

Other (OTH) AF: 0.294 AC: 621 AN: 2110

Alfa AF: 0.287 Hom.: 8594

Bravo AF: 0.284

Asia WGS AF: 0.446 AC: 1548 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	7.2
DANN	Benign	0.43
PhyloP100		0.47
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: rs2540450; hg19: chr2-202491995; COSMIC: COSV53803688; COSMIC: COSV53803688;