11-61392637-G-C

Variant names:

• chr11-61392637-G-C
• rs1215171242
• NM_001173990.3:c.6G>C

Variant summary

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

The NM_001173990.3(TMEM216):​c.6G>C​(p.Leu2Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,602 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L2L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TMEM216 NM_001173990.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.879
• Publications: 0 publications found

Genes affected

TMEM216 (HGNC:25018): (transmembrane protein 216) This locus encodes a transmembrane domain-containing protein. Mutations at this locus have been associated with Meckel-Gruber Syndrome Type 2, and Joubert Syndrome 2, also known as Cerebello-oculorenal Syndrome 2. [provided by RefSeq, Aug 2010]

TMEM216 Gene-Disease associations (from GenCC):

• Joubert syndrome 2

  Inheritance: AR Classification: 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 type 6

  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=-0.56).
• BP7: Synonymous conserved (PhyloP=0.879 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM216	NM_001173990.3	c.6G>C	p.Leu2Leu	synonymous_variant	Exon 1 of 5	ENST00000515837.7	NP_001167461.1
TMEM216	NM_001173991.3	c.6G>C	p.Leu2Leu	synonymous_variant	Exon 1 of 5		NP_001167462.1
TMEM216	NM_016499.6	c.-192G>C		5_prime_UTR_variant	Exon 1 of 5		NP_057583.2
TMEM216	NM_001330285.2	c.-192G>C		5_prime_UTR_variant	Exon 1 of 5		NP_001317214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM216	ENST00000515837.7	c.6G>C	p.Leu2Leu	synonymous_variant	Exon 1 of 5	2	NM_001173990.3	ENSP00000440638.1
TMEM216	ENST00000334888.10	c.6G>C	p.Leu2Leu	synonymous_variant	Exon 1 of 5	2		ENSP00000334844.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383602 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 682734

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31584

American (AMR) AF: 0.00 AC: 0 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078754

Other (OTH) AF: 0.00 AC: 0 AN: 57892

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.69
PhyloP100		0.88
PromoterAI		-0.25	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: rs1215171242; hg19: chr11-61160109;