15-101347562-C-G

Variant names:

• chr15-101347562-C-G
• rs2949
• ENST00000611967.4:c.*161G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138324.3(PCSK6):​c.*161G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000792 in 1,262,822 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 34)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: PCSK6 NM_138324.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.787
• Publications: 0 publications found

Genes affected

PCSK6 (HGNC:8569): (proprotein convertase subtilisin/kexin type 6) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. The encoded protease is constitutively secreted into the extracellular matrix and expressed in many tissues, including neuroendocrine, liver, gut, and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. Some of its substrates include transforming growth factor beta related proteins, proalbumin, and von Willebrand factor. This gene is thought to play a role in tumor progression and left-right patterning. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Feb 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138324.3. 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
	PCSK6	NM_002570.5	MANE Select	c.1859-15531G>C		intron	N/A	NP_002561.1
	PCSK6	NM_138324.3		c.*161G>C		3_prime_UTR	Exon 15 of 15	NP_612197.1
	PCSK6	NM_138323.3		c.*202G>C		3_prime_UTR	Exon 14 of 14	NP_612196.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK6	ENST00000611967.4	TSL:1	c.*161G>C		3_prime_UTR	Exon 15 of 15	ENSP00000477768.1
	PCSK6	ENST00000611716.5	TSL:1 MANE Select	c.1859-15531G>C		intron	N/A	ENSP00000482760.1
	PCSK6	ENST00000622483.4	TSL:1	c.1859-15531G>C		intron	N/A	ENSP00000481556.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.92e-7 AC: 1 AN: 1262822 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 609606

⚠️ 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: 28252

American (AMR) AF: 0.00 AC: 0 AN: 21708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18286

East Asian (EAS) AF: 0.00 AC: 0 AN: 34788

South Asian (SAS) AF: 0.00 AC: 0 AN: 55518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3586

European-Non Finnish (NFE) AF: 9.90e-7 AC: 1 AN: 1009962

Other (OTH) AF: 0.00 AC: 0 AN: 52046

⚠️ 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.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.085
DANN	Benign	0.32
PhyloP100		-0.79

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: rs2949; hg19: chr15-101887767;