11-117206071-G-C

Variant names:

• chr11-117206071-G-C
• rs766060344
• NM_004716.4:c.2284C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004716.4(PCSK7):​c.2284C>G​(p.Gln762Glu) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK7 NM_004716.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.792

Genes affected

PCSK7 (HGNC:8748): (proprotein convertase subtilisin/kexin type 7) 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. It encodes a type 1 membrane bound protease that is expressed in many tissues, including neuroendocrine, liver, gut, and brain. The encoded protein undergoes an initial autocatalytic processing event in the ER and then sorts to the trans-Golgi network through endosomes where a second autocatalytic event takes place and the catalytic activity is acquired. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It can process proalbumin and is thought to be responsible for the activation of HIV envelope glycoproteins gp160 and gp140. This gene has been implicated in the transcriptional regulation of housekeeping genes and plays a role in the regulation of iron metabolism. A t(11;14)(q23;q32) chromosome translocation associated with B-cell lymphoma occurs between this gene and its inverted counterpart. [provided by RefSeq, Feb 2014]

TAGLN (HGNC:11553): (transgelin) This gene encodes a shape change and transformation sensitive actin-binding protein which belongs to the calponin family. It is ubiquitously expressed in vascular and visceral smooth muscle, and is an early marker of smooth muscle differentiation. The encoded protein is thought to be involved in calcium-independent smooth muscle contraction. It acts as a tumor suppressor, and the loss of its expression is an early event in cell transformation and the development of some tumors, coinciding with cellular plasticity. The encoded protein has a domain architecture consisting of an N-terminal calponin homology (CH) domain and a C-terminal calponin-like (CLIK) domain. Mice with a knockout of the orthologous gene are viable and fertile but their vascular smooth muscle cells exhibit alterations in the distribution of the actin filament and changes in cytoskeletal organization. [provided by RefSeq, Aug 2017]

ENSG00000280143 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046072006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK7	NM_004716.4	c.2284C>G	p.Gln762Glu	missense_variant	Exon 17 of 17	ENST00000320934.8	NP_004707.2
TAGLN	NM_003186.5	c.*1712G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000392951.9	NP_003177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK7	ENST00000320934.8	c.2284C>G	p.Gln762Glu	missense_variant	Exon 17 of 17	1	NM_004716.4	ENSP00000325917.3
TAGLN	ENST00000392951.9	c.*1712G>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_003186.5	ENSP00000376678.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000493 AC: 1 AN: 202750 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 109750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000343

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.37e-7 AC: 1 AN: 1356054 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 674346

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000249

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2284C>G (p.Q762E) alteration is located in exon 17 (coding exon 15) of the PCSK7 gene. This alteration results from a C to G substitution at nucleotide position 2284, causing the glutamine (Q) at amino acid position 762 to be replaced by a glutamic acid (E). 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	Benign	0.065
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.78	N
REVEL	Benign	0.15
Sift	Benign	0.13	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.076		Gain of phosphorylation at S759 (P = 0.0982);
MVP		0.57
MPC		0.53
ClinPred		0.054	T
GERP RS		3.3
Varity_R		0.059
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs766060344; hg19: chr11-117076787;