rs59493015

Variant names:

• chr11-61392608-C-G
• rs59493015
• NM_001173990.3:c.-24C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-61392608-C-G
• chr11-61392608-C-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001173991.3(TMEM216):​c.-24C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,535,420 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (33 hom.)
• Consequence: TMEM216 NM_001173991.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.654
• Publications: 2 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 11-61392608-C-G is Benign according to our data. Variant chr11-61392608-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0112 (1703/152310) while in subpopulation AFR AF = 0.0385 (1602/41570). AF 95% confidence interval is 0.037. There are 41 homozygotes in GnomAd4. There are 796 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001173991.3. 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
	TMEM216	NM_001173990.3	MANE Select	c.-24C>G		5_prime_UTR	Exon 1 of 5	NP_001167461.1
	TMEM216	NM_001173991.3		c.-24C>G		5_prime_UTR	Exon 1 of 5	NP_001167462.1
	TMEM216	NM_016499.6		c.-221C>G		5_prime_UTR	Exon 1 of 5	NP_057583.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM216	ENST00000515837.7	TSL:2 MANE Select	c.-24C>G		5_prime_UTR	Exon 1 of 5	ENSP00000440638.1
	TMEM216	ENST00000334888.10	TSL:2	c.-24C>G		5_prime_UTR	Exon 1 of 5	ENSP00000334844.5
	TMEM216	ENST00000398979.7	TSL:1	c.-221C>G		5_prime_UTR	Exon 1 of 5	ENSP00000381950.3

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1698 AN: 152192 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00264 AC: 355 AN: 134376 AF XY: 0.00219

Gnomad AFR exome AF: 0.0438

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.00111 AC: 1532 AN: 1383110 Hom.: 33 Cov.: 31 AF XY: 0.000989 AC XY: 675 AN XY: 682488

African (AFR) AF: 0.0373 AC: 1178 AN: 31554

American (AMR) AF: 0.00253 AC: 90 AN: 35620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35728

South Asian (SAS) AF: 0.0000757 AC: 6 AN: 79212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33874

Middle Eastern (MID) AF: 0.00182 AC: 10 AN: 5490

European-Non Finnish (NFE) AF: 0.0000816 AC: 88 AN: 1078606

Other (OTH) AF: 0.00277 AC: 160 AN: 57854

GnomAD4 genome AF: 0.0112 AC: 1703 AN: 152310 Hom.: 41 Cov.: 32 AF XY: 0.0107 AC XY: 796 AN XY: 74468

African (AFR) AF: 0.0385 AC: 1602 AN: 41570

American (AMR) AF: 0.00431 AC: 66 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68028

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.000725 Hom.: 0

Bravo AF: 0.0124

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Joubert syndrome 2 (1)
-	-	1	Meckel syndrome, type 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		0.65
PromoterAI		0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=297/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs59493015; hg19: chr11-61160080;