rs1042127

Positions:

• chr6-31116393-A-C

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.1222T>G​(p.Ser408Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,600,850 control chromosomes in the GnomAD database, including 27,576 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 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 0.17 (2445 hom., cov: 31)
  • Exomes 𝑓: 0.18 (25131 hom.)
• Consequence: CDSN NM_001264.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.68

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=0.0030902624).
• BP6: Variant 6-31116393-A-C is Benign according to our data. Variant chr6-31116393-A-C is described in ClinVar as [Benign]. Clinvar id is 1236988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDSN	NM_001264.5	c.1222T>G	p.Ser408Ala	missense_variant	2/2	ENST00000376288.3
PSORS1C1	NM_014068.3	c.-229+1502A>C		intron_variant		ENST00000259881.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDSN	ENST00000376288.3	c.1222T>G	p.Ser408Ala	missense_variant	2/2	1	NM_001264.5	P1
PSORS1C1	ENST00000259881.10	c.-229+1502A>C		intron_variant		1	NM_014068.3	P2

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25917 AN: 151838 Hom.: 2450 Cov.: 31

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.187

GnomAD3 exomes AF: 0.208 AC: 46960 AN: 226292 Hom.: 5284 AF XY: 0.216 AC XY: 26400 AN XY: 122090

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.211

Gnomad SAS exome AF: 0.326

Gnomad FIN exome AF: 0.195

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.212

GnomAD4 exome AF: 0.178 AC: 258103 AN: 1448896 Hom.: 25131 Cov.: 72 AF XY: 0.185 AC XY: 132863 AN XY: 719746

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.194

Gnomad4 ASJ exome AF: 0.267

Gnomad4 EAS exome AF: 0.199

Gnomad4 SAS exome AF: 0.327

Gnomad4 FIN exome AF: 0.195

Gnomad4 NFE exome AF: 0.164

Gnomad4 OTH exome AF: 0.181

GnomAD4 genome AF: 0.170 AC: 25908 AN: 151954 Hom.: 2445 Cov.: 31 AF XY: 0.176 AC XY: 13099 AN XY: 74244

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.297

Gnomad4 EAS AF: 0.199

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.187

Alfa AF: 0.190 Hom.: 5244

Bravo AF: 0.165

TwinsUK AF: 0.150 AC: 556

ALSPAC AF: 0.136 AC: 523

ESP6500AA AF: 0.115 AC: 505

ESP6500EA AF: 0.182 AC: 1566

ExAC AF: 0.201 AC: 24270

Asia WGS AF: 0.286 AC: 996 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	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.032
Sift	Benign	0.086	T
Sift4G	Uncertain	0.060	T
Vest4		0.075
MPC		0.26
ClinPred		0.018	T
GERP RS		2.8
gMVP		0.11

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: rs1042127; hg19: chr6-31084170; COSMIC: COSV52537865; COSMIC: COSV52537865;