chr2-201633358-C-G

Variant names:

• chr2-201633358-C-G
• NM_001044385.3:c.348G>C
• TMEM237 p.Ala116Ala

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001044385.3(TMEM237):​c.348G>C​(p.Ala116Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A116A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM237 NM_001044385.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• 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: ClinGen, Ambry Genetics, G2P, PanelApp Australia, 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP7: Synonymous conserved (PhyloP=0.365 with no splicing effect.

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.348G>C	p.Ala116Ala	synonymous	Exon 6 of 13	NP_001037850.1	Q96Q45-1
	TMEM237	NM_152388.4		c.324G>C	p.Ala108Ala	synonymous	Exon 6 of 13	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.348G>C	p.Ala116Ala	synonymous	Exon 6 of 13	ENSP00000386264.2	Q96Q45-1
	TMEM237	ENST00000621467.5	TSL:1	c.222G>C	p.Ala74Ala	synonymous	Exon 6 of 13	ENSP00000480508.2	A0A087WWU1
	TMEM237	ENST00000466641.5	TSL:1	n.46G>C		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.3
DANN	Benign	0.49
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-202498081;