rs1042127

Variant names:

• chr6-31116393-A-C
• rs1042127
• NM_001264.5:c.1222T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-31116393-A-C
• chr6-31116393-A-G
• chr6-31116393-A-T

Variant summary

Our verdict is Benign. The variant received -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 40 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: Benign. The variant received -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 VariationId 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.

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.1222T>G	p.Ser408Ala	missense	Exon 2 of 2	NP_001255.4
	PSORS1C1	NM_014068.3	MANE Select	c.-229+1502A>C		intron	N/A	NP_054787.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDSN	ENST00000376288.3	TSL:1 MANE Select	c.1222T>G	p.Ser408Ala	missense	Exon 2 of 2	ENSP00000365465.2
	PSORS1C1	ENST00000259881.10	TSL:1 MANE Select	c.-229+1502A>C		intron	N/A	ENSP00000259881.9
	PSORS1C1	ENST00000479581.5	TSL:1	n.61+1502A>C		intron	N/A

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

GnomAD2 exomes AF: 0.208 AC: 46960 AN: 226292 AF XY: 0.216

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 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

African (AFR) AF: 0.111 AC: 3685 AN: 33254

American (AMR) AF: 0.194 AC: 8085 AN: 41706

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 6911 AN: 25922

East Asian (EAS) AF: 0.199 AC: 7787 AN: 39124

South Asian (SAS) AF: 0.327 AC: 27738 AN: 84922

European-Finnish (FIN) AF: 0.195 AC: 10249 AN: 52552

Middle Eastern (MID) AF: 0.248 AC: 1426 AN: 5744

European-Non Finnish (NFE) AF: 0.164 AC: 181346 AN: 1105700

Other (OTH) AF: 0.181 AC: 10876 AN: 59972

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

African (AFR) AF: 0.107 AC: 4447 AN: 41452

American (AMR) AF: 0.205 AC: 3130 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1030 AN: 3470

East Asian (EAS) AF: 0.199 AC: 1023 AN: 5134

South Asian (SAS) AF: 0.329 AC: 1584 AN: 4808

European-Finnish (FIN) AF: 0.196 AC: 2071 AN: 10568

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12078 AN: 67956

Other (OTH) AF: 0.187 AC: 394 AN: 2108

Alfa AF: 0.182 Hom.: 10333

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
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
PhyloP100		1.7
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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