rs754267246

Variant names:

• chr6-31116083-G-A
• rs754267246
• NM_001264.5:c.1532C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001264.5(CDSN):​c.1532C>T​(p.Pro511Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,611,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: CDSN NM_001264.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.54
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000301 (44/1459696) while in subpopulation MID AF = 0.000552 (3/5430). AF 95% confidence interval is 0.00034. There are 0 homozygotes in GnomAdExome4. There are 38 alleles in the male GnomAdExome4 subpopulation. Median coverage is 58. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001264.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDSN	NM_001264.5	MANE Select	c.1532C>T	p.Pro511Leu	missense	Exon 2 of 2	NP_001255.4
	PSORS1C1	NM_014068.3	MANE Select	c.-229+1192G>A		intron	N/A	NP_054787.2	Q9UIG5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDSN	ENST00000376288.3	TSL:1 MANE Select	c.1532C>T	p.Pro511Leu	missense	Exon 2 of 2	ENSP00000365465.2	Q15517
	PSORS1C1	ENST00000259881.10	TSL:1 MANE Select	c.-229+1192G>A		intron	N/A	ENSP00000259881.9	Q9UIG5-1
	PSORS1C1	ENST00000479581.5	TSL:1	n.61+1192G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000650 AC: 16 AN: 246278 AF XY: 0.000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000904

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1459696 Hom.: 0 Cov.: 58 AF XY: 0.0000523 AC XY: 38 AN XY: 726046

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000453 AC: 39 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52292

Middle Eastern (MID) AF: 0.000552 AC: 3 AN: 5430

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111582

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000102 Hom.: 0

ExAC AF: 0.0000673 AC: 8

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-1.1	T
PhyloP100		4.5
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-9.2	D
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Vest4		0.65
MutPred		0.38		Loss of disorder (P = 0.0213)
MVP		0.54
MPC		0.82
ClinPred		0.98	D
GERP RS		4.2
gMVP		0.44
Mutation Taster		=86/14	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: rs754267246; hg19: chr6-31083860; COSMIC: COSV52537261; COSMIC: COSV52537261;