17-2188494-C-A

Variant names:

• chr17-2188494-C-A
• rs199692074
• NM_017575.5:c.2891G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS2

The NM_017575.5(SMG6):​c.2891G>T​(p.Arg964Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R964H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SMG6 NM_017575.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57
• Publications: 1 publications found

Genes affected

SMG6 (HGNC:17809): (SMG6 nonsense mediated mRNA decay factor) This gene encodes a component of the telomerase ribonucleoprotein complex responsible for the replication and maintenance of chromosome ends. The encoded protein also plays a role in the nonsense-mediated mRNA decay (NMD) pathway, providing the endonuclease activity near the premature translation termination codon that is needed to initiate NMD. Alternatively spliced transcript variants encoding distinct protein isoforms have been described. [provided by RefSeq, Feb 2014]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMG6	NM_017575.5	c.2891G>T	p.Arg964Leu	missense_variant	Exon 11 of 19	ENST00000263073.11	NP_060045.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMG6	ENST00000263073.11	c.2891G>T	p.Arg964Leu	missense_variant	Exon 11 of 19	1	NM_017575.5	ENSP00000263073.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461748 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111952

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;.;T;.;.;T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;.;D;D;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.;.;.
PhyloP100		5.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.9	D;.;D;.;.;.;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.011	D;.;D;.;.;.;.;.
Sift4G	Benign	0.19	T;T;T;.;T;.;T;T
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.78
MutPred		0.51		Gain of catalytic residue at R964 (P = 0.1478);.;.;.;.;.;.;.;
MVP		0.54
MPC		0.75
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.76
gMVP		0.64
Mutation Taster		=52/48	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: rs199692074; hg19: chr17-2091788;