6-31116257-C-T

Position:

• chr6-31116257-C-T

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.1358G>A​(p.Ser453Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,614,052 control chromosomes in the GnomAD database, including 596 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (37 hom., cov: 31)
  • Exomes 𝑓: 0.013 (559 hom.)
• Consequence: CDSN NM_001264.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0100

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]

PSORS1C1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015597343).
• BP6: Variant 6-31116257-C-T is Benign according to our data. Variant chr6-31116257-C-T is described in ClinVar as [Benign]. Clinvar id is 802196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDSN	NM_001264.5	c.1358G>A	p.Ser453Asn	missense_variant	2/2	ENST00000376288.3	NP_001255.4
PSORS1C1	NM_014068.3	c.-229+1366C>T		intron_variant		ENST00000259881.10	NP_054787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDSN	ENST00000376288.3	c.1358G>A	p.Ser453Asn	missense_variant	2/2	1	NM_001264.5	ENSP00000365465.2
PSORS1C1	ENST00000259881.10	c.-229+1366C>T		intron_variant		1	NM_014068.3	ENSP00000259881.9

Frequencies

GnomAD3 genomes AF: 0.00935 AC: 1422 AN: 152102 Hom.: 37 Cov.: 31

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00896

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.0331

Gnomad SAS AF: 0.0776

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0177 AC: 4457 AN: 251228 Hom.: 122 AF XY: 0.0210 AC XY: 2854 AN XY: 135798

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00764

Gnomad ASJ exome AF: 0.0631

Gnomad EAS exome AF: 0.0120

Gnomad SAS exome AF: 0.0738

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00813

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0128 AC: 18719 AN: 1461832 Hom.: 559 Cov.: 58 AF XY: 0.0149 AC XY: 10869 AN XY: 727212

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00839

Gnomad4 ASJ exome AF: 0.0618

Gnomad4 EAS exome AF: 0.0671

Gnomad4 SAS exome AF: 0.0714

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00597

Gnomad4 OTH exome AF: 0.0159

GnomAD4 genome AF: 0.00935 AC: 1424 AN: 152220 Hom.: 37 Cov.: 31 AF XY: 0.0107 AC XY: 795 AN XY: 74422

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00895

Gnomad4 ASJ AF: 0.0559

Gnomad4 EAS AF: 0.0332

Gnomad4 SAS AF: 0.0781

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00660

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0101 Hom.: 17

Bravo AF: 0.00753

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00860 AC: 74

ExAC AF: 0.0184 AC: 2236

Asia WGS AF: 0.0320 AC: 112 AN: 3478

EpiCase AF: 0.00960

EpiControl AF: 0.00871

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 25473393) -

Peeling skin syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

CDSN-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.67
Sift	Benign	0.068	T
Sift4G	Benign	0.078	T
Vest4		0.080
MPC		0.67
ClinPred		0.0042	T
GERP RS		-0.71
gMVP		0.10

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: rs117951780; hg19: chr6-31084034;