1-159588256-C-G

Position:

• chr1-159588256-C-G

Variant summary

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

The NM_001639.4(APCS):​c.220C>G​(p.Gln74Glu) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APCS NM_001639.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.604

Genes affected

APCS (HGNC:584): (amyloid P component, serum) The protein encoded by this gene is a glycoprotein, belonging to the pentraxin family of proteins, which has a characteristic pentameric organization. These family members have considerable sequence homology which is thought to be the result of gene duplication. The binding of the encoded protein to proteins in the pathological amyloid cross-beta fold suggests its possible role as a chaperone. This protein is also thought to control the degradation of chromatin. It has been demonstrated that this protein binds to apoptotic cells at an early stage, which raises the possibility that it is involved in dealing with apoptotic cells in vivo. [provided by RefSeq, Sep 2008]

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=0.08722666).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APCS	NM_001639.4	c.220C>G	p.Gln74Glu	missense_variant	2/2	ENST00000255040.3	NP_001630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APCS	ENST00000255040.3	c.220C>G	p.Gln74Glu	missense_variant	2/2	1	NM_001639.4	ENSP00000255040.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 14, 2022

The c.220C>G (p.Q74E) alteration is located in exon 2 (coding exon 2) of the APCS gene. This alteration results from a C to G substitution at nucleotide position 220, causing the glutamine (Q) at amino acid position 74 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	0.073
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.45
DANN	Benign	0.65
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.81	L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.11
Sift	Benign	0.15	T
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.047
MutPred		0.52		Gain of disorder (P = 0.0659);
MVP		0.24
MPC		0.053
ClinPred		0.055	T
GERP RS		-5.4
Varity_R		0.29
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1658806382; hg19: chr1-159558046;