rs1208081

Variant names:

• chr2-201636725-T-C
• rs1208081
• NM_001044385.3:c.274+23A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-201636725-T-C
• chr2-201636725-T-G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001044385.3(TMEM237):​c.274+23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 1,556,314 control chromosomes in the GnomAD database, including 321,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (31972 hom., cov: 32)
  • Exomes 𝑓: 0.64 (289313 hom.)
• Consequence: TMEM237 NM_001044385.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.499
• Publications: 16 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 -16 ACMG points.

• BP6: Variant 2-201636725-T-C is Benign according to our data. Variant chr2-201636725-T-C is described in ClinVar as Benign. ClinVar VariationId is 257317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.664 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM237	NM_001044385.3	MANE Select	c.274+23A>G		intron	N/A	NP_001037850.1
	TMEM237	NM_152388.4		c.250+23A>G		intron	N/A	NP_689601.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM237	ENST00000409883.7	TSL:5 MANE Select	c.274+23A>G		intron	N/A	ENSP00000386264.2
	TMEM237	ENST00000621467.5	TSL:1	c.148+23A>G		intron	N/A	ENSP00000480508.2
	TMEM237	ENST00000480124.1	TSL:3	n.204A>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.645 AC: 98076 AN: 152022 Hom.: 31947 Cov.: 32

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.691

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.648

GnomAD2 exomes AF: 0.617 AC: 105859 AN: 171686 AF XY: 0.622

Gnomad AFR exome AF: 0.671

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.707

Gnomad EAS exome AF: 0.375

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.659

Gnomad OTH exome AF: 0.644

GnomAD4 exome AF: 0.640 AC: 898068 AN: 1404174 Hom.: 289313 Cov.: 37 AF XY: 0.640 AC XY: 443849 AN XY: 693516

African (AFR) AF: 0.667 AC: 21479 AN: 32206

American (AMR) AF: 0.555 AC: 19815 AN: 35684

Ashkenazi Jewish (ASJ) AF: 0.697 AC: 17723 AN: 25414

East Asian (EAS) AF: 0.370 AC: 13878 AN: 37486

South Asian (SAS) AF: 0.632 AC: 50374 AN: 79752

European-Finnish (FIN) AF: 0.613 AC: 29313 AN: 47840

Middle Eastern (MID) AF: 0.669 AC: 3514 AN: 5250

European-Non Finnish (NFE) AF: 0.651 AC: 704982 AN: 1082318

Other (OTH) AF: 0.635 AC: 36990 AN: 58224

GnomAD4 genome AF: 0.645 AC: 98153 AN: 152140 Hom.: 31972 Cov.: 32 AF XY: 0.641 AC XY: 47641 AN XY: 74378

African (AFR) AF: 0.670 AC: 27837 AN: 41518

American (AMR) AF: 0.611 AC: 9350 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 2399 AN: 3472

East Asian (EAS) AF: 0.372 AC: 1917 AN: 5156

South Asian (SAS) AF: 0.640 AC: 3088 AN: 4826

European-Finnish (FIN) AF: 0.591 AC: 6244 AN: 10560

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.663 AC: 45068 AN: 67988

Other (OTH) AF: 0.649 AC: 1374 AN: 2116

Alfa AF: 0.653 Hom.: 110994

Bravo AF: 0.646

Asia WGS AF: 0.539 AC: 1877 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	23
DANN	Benign	0.91
PhyloP100		0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1208081; hg19: chr2-202501448; COSMIC: COSV53805105; COSMIC: COSV53805105;