16-75556260-C-G

Variant names:

• chr16-75556260-C-G
• rs115739052
• ENST00000562410.5:n.-51G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001077416.2(TMEM231):​c.12G>C​(p.Arg4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000325 in 1,230,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: TMEM231 NM_001077416.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.110
• Publications: 0 publications found

Genes affected

TMEM231 (HGNC:37234): (transmembrane protein 231) This gene encodes a transmembrane protein, which is a component of the B9 complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. Mutations in this gene cause Joubert syndrome (JBTS). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

TMEM231 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 20

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• Meckel syndrome, type 11

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome III

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000259992 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077416.2. 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
	TMEM231	NM_001077416.2		c.12G>C	p.Arg4Ser	missense	Exon 1 of 6	NP_001070884.2	Q9H6L2
	TMEM231	NM_001077418.3	MANE Select	c.-51G>C		upstream_gene	N/A	NP_001070886.1	Q9H6L2-1
	TMEM231	NR_074083.2		n.-8G>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM231	ENST00000562410.5	TSL:1	n.-51G>C		non_coding_transcript_exon	Exon 1 of 7	ENSP00000454582.1	H3BMW7
	TMEM231	ENST00000562410.5	TSL:1	n.-51G>C		5_prime_UTR	Exon 1 of 7	ENSP00000454582.1	H3BMW7
	TMEM231	ENST00000870301.1		c.-51G>C		5_prime_UTR	Exon 1 of 7	ENSP00000540360.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000325 AC: 4 AN: 1230506 Hom.: 0 Cov.: 31 AF XY: 0.00000336 AC XY: 2 AN XY: 594892

African (AFR) AF: 0.00 AC: 0 AN: 24500

American (AMR) AF: 0.00 AC: 0 AN: 13716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17338

East Asian (EAS) AF: 0.00 AC: 0 AN: 29230

South Asian (SAS) AF: 0.00 AC: 0 AN: 56104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4978

European-Non Finnish (NFE) AF: 0.00000398 AC: 4 AN: 1004140

Other (OTH) AF: 0.00 AC: 0 AN: 50890

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.7
DANN	Benign	0.87
PhyloP100		-0.11
PromoterAI		0.016	Neutral

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: rs115739052; hg19: chr16-75590158;