6-166307319-G-C

Variant names:

• chr6-166307319-G-C
• rs199941091
• NM_175922.4:c.824C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_175922.4(PRR18):​c.824C>G​(p.Ser275Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,556,366 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S275A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: PRR18 NM_175922.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0700
• Publications: 1 publications found

Genes affected

PRR18 (HGNC:28574): (proline rich 18)

LOC107986669 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01952079).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRR18	NM_175922.4	c.824C>G	p.Ser275Cys	missense_variant	Exon 1 of 1	ENST00000322583.5	NP_787118.2
LOC107986669	XR_001744464.2	n.-229G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRR18	ENST00000322583.5	c.824C>G	p.Ser275Cys	missense_variant	Exon 1 of 1	6	NM_175922.4	ENSP00000319590.3

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152080 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000963 AC: 161 AN: 167242 AF XY: 0.000989

Gnomad AFR exome AF: 0.000278

Gnomad AMR exome AF: 0.0000359

Gnomad ASJ exome AF: 0.000494

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00165

Gnomad NFE exome AF: 0.00168

Gnomad OTH exome AF: 0.000473

GnomAD4 exome AF: 0.00121 AC: 1696 AN: 1404178 Hom.: 3 Cov.: 58 AF XY: 0.00122 AC XY: 850 AN XY: 696844

African (AFR) AF: 0.000268 AC: 8 AN: 29864

American (AMR) AF: 0.000201 AC: 8 AN: 39708

Ashkenazi Jewish (ASJ) AF: 0.000402 AC: 10 AN: 24904

East Asian (EAS) AF: 0.00 AC: 0 AN: 35470

South Asian (SAS) AF: 0.000420 AC: 34 AN: 81010

European-Finnish (FIN) AF: 0.00108 AC: 40 AN: 37144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5320

European-Non Finnish (NFE) AF: 0.00141 AC: 1541 AN: 1092294

Other (OTH) AF: 0.000941 AC: 55 AN: 58464

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.00105 AC XY: 78 AN XY: 74388

African (AFR) AF: 0.000265 AC: 11 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00190 AC: 129 AN: 67972

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.000672

ExAC AF: 0.000907 AC: 106

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.824C>G (p.S275C) alteration is located in exon 1 (coding exon 1) of the PRR18 gene. This alteration results from a C to G substitution at nucleotide position 824, causing the serine (S) at amino acid position 275 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	0.28
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.089	T
Eigen	Benign	0.085
Eigen_PC	Benign	-0.0023
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.070
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.17
MVP		0.24
MPC		1.9
ClinPred		0.056	T
GERP RS		1.2
Varity_R		0.22
gMVP		0.070
Mutation Taster		=89/11	polymorphism

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: rs199941091; hg19: chr6-166720807;