rs7742033

Positions:

• chr6-31117449-G-A

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.166C>T​(p.Leu56Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,557,208 control chromosomes in the GnomAD database, including 341 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 Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.022 (71 hom., cov: 33)
  • Exomes 𝑓: 0.012 (270 hom.)
• Consequence: CDSN NM_001264.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00900

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=0.00291425).
• BP6: Variant 6-31117449-G-A is Benign according to our data. Variant chr6-31117449-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1321061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDSN	NM_001264.5	c.166C>T	p.Leu56Phe	missense_variant	2/2	ENST00000376288.3	NP_001255.4
PSORS1C1	NM_014068.3	c.-229+2558G>A		intron_variant		ENST00000259881.10	NP_054787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDSN	ENST00000376288.3	c.166C>T	p.Leu56Phe	missense_variant	2/2	1	NM_001264.5	ENSP00000365465	P1
PSORS1C1	ENST00000259881.10	c.-229+2558G>A		intron_variant		1	NM_014068.3	ENSP00000259881	P2

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3318 AN: 152180 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.0488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.00970

Gnomad OTH AF: 0.0336

GnomAD3 exomes AF: 0.0160 AC: 2574 AN: 160586 Hom.: 53 AF XY: 0.0166 AC XY: 1418 AN XY: 85536

Gnomad AFR exome AF: 0.0467

Gnomad AMR exome AF: 0.0130

Gnomad ASJ exome AF: 0.0541

Gnomad EAS exome AF: 0.000753

Gnomad SAS exome AF: 0.0256

Gnomad FIN exome AF: 0.000633

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0260

GnomAD4 exome AF: 0.0121 AC: 17019 AN: 1404910 Hom.: 270 Cov.: 54 AF XY: 0.0126 AC XY: 8717 AN XY: 693598

Gnomad4 AFR exome AF: 0.0470

Gnomad4 AMR exome AF: 0.0147

Gnomad4 ASJ exome AF: 0.0527

Gnomad4 EAS exome AF: 0.000687

Gnomad4 SAS exome AF: 0.0244

Gnomad4 FIN exome AF: 0.000882

Gnomad4 NFE exome AF: 0.00924

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0218 AC: 3318 AN: 152298 Hom.: 71 Cov.: 33 AF XY: 0.0217 AC XY: 1614 AN XY: 74474

Gnomad4 AFR AF: 0.0488

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.0490

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0186

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00970

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.0152 Hom.: 65

Bravo AF: 0.0247

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.0378 AC: 134

ESP6500EA AF: 0.00788 AC: 54

ExAC AF: 0.0102 AC: 1129

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2023	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.027
Sift	Benign	0.060	T
Sift4G	Benign	0.087	T
Vest4		0.13
MPC		0.34
ClinPred		0.0059	T
GERP RS		2.0
gMVP		0.38

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: rs7742033; hg19: chr6-31085226;