2-238068154-G-T

Variant names:

• chr2-238068154-G-T
• rs779932782
• NM_016510.7:c.292G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016510.7(SCLY):​c.292G>T​(p.Gly98Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. 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. G98R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCLY NM_016510.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.15
• Publications: 0 publications found

Genes affected

SCLY (HGNC:18161): (selenocysteine lyase) Selenocysteine lyase (SCLY; EC 4.4.1.16) catalyzes the pyridoxal 5-prime phosphate-dependent conversion of L-selenocysteine to L-alanine and elemental selenium (Mihara et al., 2000 [PubMed 10692412]).[supplied by OMIM, Mar 2008]

UBE2F-SCLY (HGNC:48339): (UBE2F-SCLY readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring UBE2F (ubiquitin-conjugating enzyme E2F) and SCLY (selenocysteine lyase) genes on chromosome 2. The read-through transcript is a candidate for non-sense mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016510.7. 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
	SCLY	NM_016510.7	MANE Select	c.292G>T	p.Gly98Trp	missense	Exon 3 of 12	NP_057594.5
	UBE2F-SCLY	NR_037904.1		n.868G>T		non_coding_transcript_exon	Exon 10 of 19

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCLY	ENST00000254663.12	TSL:1 MANE Select	c.292G>T	p.Gly98Trp	missense	Exon 3 of 12	ENSP00000254663.7	Q96I15-1
	SCLY	ENST00000409736.6	TSL:1	c.292G>T	p.Gly98Trp	missense	Exon 3 of 8	ENSP00000387162.2	Q96I15-2
	UBE2F-SCLY	ENST00000449191.1	TSL:3	n.*465G>T		non_coding_transcript_exon	Exon 11 of 11	ENSP00000456827.1	H3BSR4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453868 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 723386

⚠️ 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: 33178

American (AMR) AF: 0.00 AC: 0 AN: 43872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39348

South Asian (SAS) AF: 0.00 AC: 0 AN: 85022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107130

Other (OTH) AF: 0.00 AC: 0 AN: 60136

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		7.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.91		Loss of disorder (P = 0.036)
MVP		0.93
MPC		0.48
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=26/74	disease causing

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: rs779932782; hg19: chr2-238976795;