2-238061049-G-T

Variant names:

• chr2-238061049-G-T
• rs1287803598
• NM_016510.7:c.-6G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016510.7(SCLY):​c.-6G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000244 in 1,230,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: SCLY NM_016510.7 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.853

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10419941).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCLY	NM_016510.7	c.-6G>T		5_prime_UTR_variant	Exon 1 of 12	ENST00000254663.12	NP_057594.5
UBE2F-SCLY	NR_037904.1	n.666-3308G>T		intron_variant	Intron 8 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCLY	ENST00000254663	c.-6G>T		5_prime_UTR_variant	Exon 1 of 12	1	NM_016510.7	ENSP00000254663.7
UBE2F-SCLY	ENST00000449191.1	n.*263-3308G>T		intron_variant	Intron 9 of 10	3		ENSP00000456827.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000244 AC: 3 AN: 1230428 Hom.: 0 Cov.: 30 AF XY: 0.00000167 AC XY: 1 AN XY: 597082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000297

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.19G>T (p.A7S) alteration is located in exon 1 (coding exon 1) of the SCLY gene. This alteration results from a G to T substitution at nucleotide position 19, causing the alanine (A) at amino acid position 7 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.6
DANN	Benign	0.93
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.32	T;.
M_CAP	Benign	0.00059	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.21	N;N
REVEL	Benign	0.011
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;T
Vest4		0.11
MutPred		0.17		Gain of glycosylation at A7 (P = 0.0015);Gain of glycosylation at A7 (P = 0.0015);
MVP		0.18
MPC		0.24
ClinPred		0.18	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1287803598; hg19: chr2-238969690;