16-67228863-C-T

Position:

• chr16-67228863-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_014187.4(TMEM208):​c.366C>T​(p.Val122Val) variant causes a synonymous change. The variant allele was found at a frequency of 0.000967 in 1,614,020 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (6 hom.)
• Consequence: TMEM208 NM_014187.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.41

Genes affected

TMEM208 (HGNC:25015): (transmembrane protein 208) This gene encodes a highly conserved protein which is localized in the endoplasmic reticulum (ER). The protein is linked to autophagy and ER stress. Knockdown of this gene increased autophagy and triggered ER stress. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 16-67228863-C-T is Benign according to our data. Variant chr16-67228863-C-T is described in ClinVar as [Benign]. Clinvar id is 791557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM208	NM_014187.4	c.366C>T	p.Val122Val	synonymous_variant	5/6	ENST00000304800.14	NP_054906.2
TMEM208	NM_001318217.2	c.156C>T	p.Val52Val	synonymous_variant	5/6		NP_001305146.1
TMEM208	NR_134524.2	n.481C>T		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM208	ENST00000304800.14	c.366C>T	p.Val122Val	synonymous_variant	5/6	1	NM_014187.4	ENSP00000305892.9

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 530 AN: 152222 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00130 AC: 323 AN: 249208 Hom.: 0 AF XY: 0.00107 AC XY: 145 AN XY: 135186

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.000705 AC: 1031 AN: 1461680 Hom.: 6 Cov.: 32 AF XY: 0.000675 AC XY: 491 AN XY: 727134

Gnomad4 AFR exome AF: 0.0137

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000305

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00347 AC: 529 AN: 152340 Hom.: 1 Cov.: 32 AF XY: 0.00346 AC XY: 258 AN XY: 74494

Gnomad4 AFR AF: 0.0112

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00204 Hom.: 1

Bravo AF: 0.00391

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.9
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34502419; hg19: chr16-67262766;