X-48832068-C-G

Position:

• chrX-48832068-C-G

Variant summary

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

The NM_013271.5(PCSK1N):​c.388G>C​(p.Asp130His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000498 in 1,004,903 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000050 (0 hom. 1 hem.)
• Consequence: PCSK1N NM_013271.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21

Genes affected

PCSK1N (HGNC:17301): (proprotein convertase subtilisin/kexin type 1 inhibitor) The protein encoded by this gene functions as an inhibitor of prohormone convertase 1, which regulates the proteolytic cleavage of neuroendocrine peptide precursors. The proprotein is further processed into multiple short peptides. A polymorphism within this gene may be associated with obesity. [provided by RefSeq, Aug 2013]

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
PCSK1N	NM_013271.5	c.388G>C	p.Asp130His	missense_variant	2/3	ENST00000218230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK1N	ENST00000218230.6	c.388G>C	p.Asp130His	missense_variant	2/3	1	NM_013271.5	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000498 AC: 5 AN: 1004903 Hom.: 0 Cov.: 32 AF XY: 0.00000307 AC XY: 1 AN XY: 325537

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000446

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: 0.00000373

Gnomad4 OTH exome AF: 0.0000235

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000113

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

Sep 30, 2022

The c.388G>C (p.D130H) alteration is located in exon 2 (coding exon 2) of the PCSK1N gene. This alteration results from a G to C substitution at nucleotide position 388, causing the aspartic acid (D) at amino acid position 130 to be replaced by a histidine (H). 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
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.98	N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Benign	0.24
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.025	D
Polyphen		0.96	D
Vest4		0.32
MutPred		0.60		Loss of helix (P = 0.0558);
MVP		0.73
MPC		2.0
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.52
gMVP		0.22

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: rs2063174810; hg19: chrX-48690478;