rs2242407

Variant names:

• chr16-75539986-T-C
• rs2242407
• ENST00000562410.5:n.*761A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000562410.5(TMEM231):​n.*761A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,599,648 control chromosomes in the GnomAD database, including 52,187 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (4830 hom., cov: 32)
  • Exomes 𝑓: 0.25 (47357 hom.)
• Consequence: TMEM231 ENST00000562410.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.467
• Publications: 16 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: G2P, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000260092 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.*8A>G		3_prime_UTR_variant	Exon 7 of 7	ENST00000258173.11	NP_001070886.1
TMEM231	NR_074083.2	n.1125A>G		non_coding_transcript_exon_variant	Exon 7 of 7
TMEM231	NM_001077416.2	c.*8A>G		3_prime_UTR_variant	Exon 6 of 6		NP_001070884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000562410.5	n.*761A>G		non_coding_transcript_exon_variant	Exon 7 of 7	1		ENSP00000454582.1
TMEM231	ENST00000258173.11	c.*8A>G		3_prime_UTR_variant	Exon 7 of 7	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.*8A>G		3_prime_UTR_variant	Exon 6 of 6	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.*8A>G		3_prime_UTR_variant	Exon 6 of 6	5		ENSP00000457254.1
TMEM231	ENST00000562410.5	n.*761A>G		3_prime_UTR_variant	Exon 7 of 7	1		ENSP00000454582.1
ENSG00000260092	ENST00000460606.1	n.157+2616A>G		intron_variant	Intron 2 of 4	1		ENSP00000457544.1
TMEM231	ENST00000570006.5	n.*339A>G		downstream_gene_variant		5		ENSP00000455520.1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 37791 AN: 149860 Hom.: 4826 Cov.: 32

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.230

GnomAD2 exomes AF: 0.234 AC: 56179 AN: 240376 AF XY: 0.237

Gnomad AFR exome AF: 0.246

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.201

Gnomad FIN exome AF: 0.303

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.241

GnomAD4 exome AF: 0.252 AC: 365984 AN: 1449680 Hom.: 47357 Cov.: 31 AF XY: 0.252 AC XY: 181851 AN XY: 720562

African (AFR) AF: 0.246 AC: 8164 AN: 33234

American (AMR) AF: 0.127 AC: 5565 AN: 43870

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4493 AN: 25580

East Asian (EAS) AF: 0.215 AC: 8522 AN: 39610

South Asian (SAS) AF: 0.229 AC: 19408 AN: 84620

European-Finnish (FIN) AF: 0.309 AC: 16338 AN: 52938

Middle Eastern (MID) AF: 0.226 AC: 1071 AN: 4738

European-Non Finnish (NFE) AF: 0.260 AC: 287708 AN: 1105222

Other (OTH) AF: 0.246 AC: 14715 AN: 59868

GnomAD4 genome AF: 0.252 AC: 37817 AN: 149968 Hom.: 4830 Cov.: 32 AF XY: 0.251 AC XY: 18380 AN XY: 73354

African (AFR) AF: 0.255 AC: 10088 AN: 39558

American (AMR) AF: 0.182 AC: 2758 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 605 AN: 3470

East Asian (EAS) AF: 0.227 AC: 1174 AN: 5164

South Asian (SAS) AF: 0.224 AC: 1077 AN: 4808

European-Finnish (FIN) AF: 0.308 AC: 3255 AN: 10558

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17961 AN: 67922

Other (OTH) AF: 0.233 AC: 487 AN: 2094

Alfa AF: 0.252 Hom.: 2912

Asia WGS AF: 0.284 AC: 983 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2016

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 provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.068
DANN	Benign	0.33
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: rs2242407; hg19: chr16-75573884; COSMIC: COSV50737805; COSMIC: COSV50737805;