6-31764523-C-T

Variant names:

• chr6-31764523-C-T
• rs777749400
• NM_001039651.2:c.529C>T

Variant summary

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

The NM_001039651.2(SAPCD1):​c.529C>T​(p.Arg177Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000826 in 1,610,916 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (1 hom.)
• Consequence: SAPCD1 NM_001039651.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.230

Genes affected

SAPCD1 (HGNC:13938): (suppressor APC domain containing 1)

MSH5-SAPCD1 (HGNC:41994): (MSH5-SAPCD1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring mutS homolog 5 (MSH5) and chromosome 6 open reading frame 26 (C6orf26) genes. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

SAPCD1-AS1 (HGNC:39824): (SAPCD1 antisense RNA 1)

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=0.048752427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAPCD1	NM_001039651.2	c.529C>T	p.Arg177Cys	missense_variant	Exon 5 of 5	ENST00000415669.4	NP_001034740.1
MSH5-SAPCD1	NR_037846.1	n.3736C>T		non_coding_transcript_exon_variant	Exon 29 of 29
SAPCD1-AS1	NR_126423.1	n.248G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAPCD1	ENST00000415669.4	c.529C>T	p.Arg177Cys	missense_variant	Exon 5 of 5	1	NM_001039651.2	ENSP00000411948.2
MSH5-SAPCD1	ENST00000493662.6	n.*1052C>T		non_coding_transcript_exon_variant	Exon 29 of 29	1		ENSP00000417871.2
MSH5-SAPCD1	ENST00000493662.6	n.*1052C>T		3_prime_UTR_variant	Exon 29 of 29	1		ENSP00000417871.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.0000599 AC: 15 AN: 250442 Hom.: 0 AF XY: 0.0000591 AC XY: 8 AN XY: 135442

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.0000836 AC: 122 AN: 1458710 Hom.: 1 Cov.: 31 AF XY: 0.0000772 AC XY: 56 AN XY: 725792

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.000897

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74358

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.0000225 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000988 AC: 12

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.529C>T (p.R177C) alteration is located in exon 5 (coding exon 5) of the SAPCD1 gene. This alteration results from a C to T substitution at nucleotide position 529, causing the arginine (R) at amino acid position 177 to be replaced by a cysteine (C). 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	0.13
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0046	T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.088	N
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	0.020	N;N
REVEL	Benign	0.063
Sift	Benign	0.14	T;T
Sift4G	Uncertain	0.026	D;D
Polyphen		0.97	.;D
Vest4		0.14
MutPred		0.27		.;Loss of solvent accessibility (P = 0.0111);
MVP		0.24
MPC		0.58
ClinPred		0.081	T
GERP RS		1.2
Varity_R		0.078
gMVP		0.11

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: rs777749400; hg19: chr6-31732300; COSMIC: COSV100991930; COSMIC: COSV100991930;