17-2300159-A-G

Variant names:

• chr17-2300159-A-G
• rs216193
• NM_017575.5:c.594T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_017575.5(SMG6):​c.594T>C​(p.Ala198Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,613,554 control chromosomes in the GnomAD database, including 305,590 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 0.56 (24567 hom., cov: 31)
  • Exomes 𝑓: 0.62 (281023 hom.)
• Consequence: SMG6 NM_017575.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.437
• Publications: 48 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP7: Synonymous conserved (PhyloP=-0.437 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017575.5. 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
	SMG6	NM_017575.5	MANE Select	c.594T>C	p.Ala198Ala	synonymous	Exon 2 of 19	NP_060045.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMG6	ENST00000263073.11	TSL:1 MANE Select	c.594T>C	p.Ala198Ala	synonymous	Exon 2 of 19	ENSP00000263073.5	Q86US8-1
	SMG6	ENST00000883972.1		c.594T>C	p.Ala198Ala	synonymous	Exon 2 of 18	ENSP00000554031.1

Frequencies

GnomAD3 genomes AF: 0.560 AC: 84821 AN: 151598 Hom.: 24552 Cov.: 31

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.572

GnomAD2 exomes AF: 0.609 AC: 153027 AN: 251412 AF XY: 0.609

Gnomad AFR exome AF: 0.394

Gnomad AMR exome AF: 0.655

Gnomad ASJ exome AF: 0.669

Gnomad EAS exome AF: 0.682

Gnomad FIN exome AF: 0.635

Gnomad NFE exome AF: 0.615

Gnomad OTH exome AF: 0.609

GnomAD4 exome AF: 0.617 AC: 902565 AN: 1461834 Hom.: 281023 Cov.: 88 AF XY: 0.616 AC XY: 447729 AN XY: 727214

African (AFR) AF: 0.381 AC: 12753 AN: 33478

American (AMR) AF: 0.650 AC: 29079 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 17265 AN: 26136

East Asian (EAS) AF: 0.725 AC: 28787 AN: 39700

South Asian (SAS) AF: 0.570 AC: 49166 AN: 86258

European-Finnish (FIN) AF: 0.638 AC: 34067 AN: 53364

Middle Eastern (MID) AF: 0.552 AC: 3185 AN: 5768

European-Non Finnish (NFE) AF: 0.622 AC: 691590 AN: 1112012

Other (OTH) AF: 0.607 AC: 36673 AN: 60396

GnomAD4 genome AF: 0.559 AC: 84879 AN: 151720 Hom.: 24567 Cov.: 31 AF XY: 0.564 AC XY: 41798 AN XY: 74142

African (AFR) AF: 0.403 AC: 16632 AN: 41314

American (AMR) AF: 0.601 AC: 9163 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 2262 AN: 3470

East Asian (EAS) AF: 0.695 AC: 3582 AN: 5154

South Asian (SAS) AF: 0.567 AC: 2725 AN: 4810

European-Finnish (FIN) AF: 0.644 AC: 6775 AN: 10528

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.616 AC: 41816 AN: 67890

Other (OTH) AF: 0.571 AC: 1206 AN: 2112

Alfa AF: 0.593 Hom.: 48798

Bravo AF: 0.551

Asia WGS AF: 0.566 AC: 1967 AN: 3478

EpiCase AF: 0.617

EpiControl AF: 0.611

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.54
DANN	Benign	0.56
PhyloP100		-0.44
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: rs216193; hg19: chr17-2203453; COSMIC: COSV53963167; COSMIC: COSV53963167;