chr5-42800763-C-G

Position:

• chr5-42800763-C-G

Variant summary

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

The NM_005410.4(SELENOP):​c.1103G>C​(p.Arg368Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R368H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SELENOP NM_005410.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.558

Genes affected

SELENOP (HGNC:10751): (selenoprotein P) This gene encodes a selenoprotein that is predominantly expressed in the liver and secreted into the plasma. This selenoprotein is unique in that it contains multiple selenocysteine (Sec) residues per polypeptide (10 in human), and accounts for most of the selenium in plasma. It has been implicated as an extracellular antioxidant, and in the transport of selenium to extra-hepatic tissues via apolipoprotein E receptor-2 (apoER2). Mice lacking this gene exhibit neurological dysfunction, suggesting its importance in normal brain function. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. The mRNA for this selenoprotein contains two SECIS elements. The use of alternative polyadenylation sites, one located in between the two SECIS elements, results in two populations of mRNAs containing either both (predominant) or just the upstream SECIS element (PMID:27881738). Alternatively spliced transcript variants have also been found for this gene. [provided by RefSeq, Oct 2018]

CCDC152 (HGNC:34438): (coiled-coil domain containing 152)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SELENOP	NM_005410.4	c.1103G>C	p.Arg368Pro	missense_variant	5/5	ENST00000514985.6
CCDC152	NM_001134848.2	c.*982C>G		3_prime_UTR_variant	9/9	ENST00000361970.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENOP	ENST00000514985.6	c.1103G>C	p.Arg368Pro	missense_variant	5/5	1	NM_005410.4	P1
CCDC152	ENST00000361970.10	c.*982C>G		3_prime_UTR_variant	9/9	1	NM_001134848.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2024

The c.1103G>C (p.R368P) alteration is located in exon 5 (coding exon 4) of the SEPP1 gene. This alteration results from a G to C substitution at nucleotide position 1103, causing the arginine (R) at amino acid position 368 to be replaced by a proline (P). 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	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.029	T;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.34	.;.;T
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.17	N;N;N
REVEL	Benign	0.041
Sift	Uncertain	0.018	D;D;D
Sift4G	Benign	0.099	T;T;T
MutPred		0.43		Gain of ubiquitination at K370 (P = 0.0357);Gain of ubiquitination at K370 (P = 0.0357);Gain of ubiquitination at K370 (P = 0.0357);
MVP		0.092
MPC		0.086
ClinPred		0.15	T
GERP RS		1.4
Varity_R		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-42800865;