rs3095318

Positions:

• chr6-31120368-T-A
• chr6-31120368-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001264.5(CDSN):​c.52A>T​(p.Met18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,592,424 control chromosomes in the GnomAD database, including 40,768 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2244 hom., cov: 30)
  • Exomes 𝑓: 0.22 (38524 hom.)
• Consequence: CDSN NM_001264.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0190

Genes affected

CDSN (HGNC:1802): (corneodesmosin) This gene encodes a protein found in corneodesmosomes, which localize to human epidermis and other cornified squamous epithelia. The encoded protein undergoes a series of cleavages during corneocyte maturation. This gene is highly polymorphic in human populations, and variation has been associated with skin diseases such as psoriasis, hypotrichosis and peeling skin syndrome. The gene is located in the major histocompatibility complex (MHC) class I region on chromosome 6. [provided by RefSeq, Dec 2014]

PSORS1C1 (HGNC:17202): (psoriasis susceptibility 1 candidate 1) This gene is one of several genes thought to confer susceptibility to psoriasis and systemic sclerosis, located on chromosome 6 near the major histocompatibility complex (MHC) class I region. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032334626).
• BP6: Variant 6-31120368-T-A is Benign according to our data. Variant chr6-31120368-T-A is described in ClinVar as [Benign]. Clinvar id is 1244640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDSN	NM_001264.5	c.52A>T	p.Met18Leu	missense_variant	1/2	ENST00000376288.3
PSORS1C1	NM_014068.3	c.-228-5308T>A		intron_variant		ENST00000259881.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDSN	ENST00000376288.3	c.52A>T	p.Met18Leu	missense_variant	1/2	1	NM_001264.5	P1
PSORS1C1	ENST00000259881.10	c.-228-5308T>A		intron_variant		1	NM_014068.3	P2

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24559 AN: 151890 Hom.: 2242 Cov.: 30

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0960

Gnomad EAS AF: 0.0669

Gnomad SAS AF: 0.0640

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0764

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.134

GnomAD3 exomes AF: 0.146 AC: 31216 AN: 214444 Hom.: 2876 AF XY: 0.147 AC XY: 16929 AN XY: 115452

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.0691

Gnomad ASJ exome AF: 0.0946

Gnomad EAS exome AF: 0.0971

Gnomad SAS exome AF: 0.0648

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.217 AC: 312032 AN: 1440414 Hom.: 38524 Cov.: 41 AF XY: 0.211 AC XY: 151064 AN XY: 714412

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.0741

Gnomad4 ASJ exome AF: 0.0982

Gnomad4 EAS exome AF: 0.0430

Gnomad4 SAS exome AF: 0.0668

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.162 AC: 24587 AN: 152010 Hom.: 2244 Cov.: 30 AF XY: 0.153 AC XY: 11365 AN XY: 74278

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.0960

Gnomad4 EAS AF: 0.0670

Gnomad4 SAS AF: 0.0642

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.133

Alfa AF: 0.201 Hom.: 2592

Bravo AF: 0.160

TwinsUK AF: 0.262 AC: 973

ALSPAC AF: 0.280 AC: 1079

ESP6500AA AF: 0.140 AC: 615

ESP6500EA AF: 0.213 AC: 1831

ExAC AF: 0.136 AC: 16375

Asia WGS AF: 0.0700 AC: 246 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.4
DANN	Benign	0.83
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.065
Sift	Benign	0.39	T
Sift4G	Benign	1.0	T
Vest4		0.066
MutPred		0.31		Loss of MoRF binding (P = 0.0694);
MPC		0.29
ClinPred		0.00089	T
GERP RS		0.51
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3095318; hg19: chr6-31088145; COSMIC: COSV52548295; COSMIC: COSV52548295;