2-201633304-T-C

Variant names:

• chr2-201633304-T-C
• rs78297522
• NM_001044385.3:c.395+7A>G

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.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
• Publications: 3 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: Ambry Genetics, G2P, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
• 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 2-201633304-T-C is Benign according to our data. Variant chr2-201633304-T-C is described in ClinVar as Benign. ClinVar VariationId is 130593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001044385.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM237	NM_001044385.3	MANE Select	c.395+7A>G		splice_region intron	N/A	NP_001037850.1	Q96Q45-1
	TMEM237	NM_152388.4		c.371+7A>G		splice_region intron	N/A	NP_689601.2	Q96Q45-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM237	ENST00000409883.7	TSL:5 MANE Select	c.395+7A>G		splice_region intron	N/A	ENSP00000386264.2	Q96Q45-1
	TMEM237	ENST00000621467.5	TSL:1	c.269+7A>G		splice_region intron	N/A	ENSP00000480508.2	A0A087WWU1
	TMEM237	ENST00000466641.5	TSL:1	n.93+7A>G		splice_region intron	N/A

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

GnomAD2 exomes AF: 0.00809 AC: 1826 AN: 225756 AF XY: 0.00703

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 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

African (AFR) AF: 0.0547 AC: 1808 AN: 33058

American (AMR) AF: 0.00342 AC: 146 AN: 42630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25750

East Asian (EAS) AF: 0.0326 AC: 1278 AN: 39148

South Asian (SAS) AF: 0.000848 AC: 70 AN: 82590

European-Finnish (FIN) AF: 0.0000387 AC: 2 AN: 51616

Middle Eastern (MID) AF: 0.00227 AC: 13 AN: 5736

European-Non Finnish (NFE) AF: 0.000125 AC: 138 AN: 1103116

Other (OTH) AF: 0.00591 AC: 353 AN: 59762

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

African (AFR) AF: 0.0581 AC: 2411 AN: 41532

American (AMR) AF: 0.00700 AC: 107 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0381 AC: 197 AN: 5172

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68028

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.00558 Hom.: 13

Bravo AF: 0.0216

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Joubert syndrome 14 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.7
DANN	Benign	0.62
PhyloP100		0.0050
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs78297522; hg19: chr2-202498027;