chr18-31130588-C-T

Variant names:

• chr18-31130588-C-T
• rs781222904
• NM_024421.2:c.2611G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024421.2(DSC1):​c.2611G>A​(p.Glu871Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E871Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC1 NM_024421.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.10
• Publications: 1 publications found

Genes affected

DSC1 (HGNC:3035): (desmocollin 1) The protein encoded by this gene is a calcium-dependent glycoprotein that is a member of the desmocollin subfamily of the cadherin superfamily. These desmosomal family members, along with the desmogleins, are found primarily in epithelial cells where they constitute the adhesive proteins of the desmosome cell-cell junction and are required for cell adhesion and desmosome formation. A subtype of IgA pemphigus, a life-threatening autoimmune disease, is characterized by the presence of autoantibodies that target the encoded protein. The desmosomal family members are arranged in two clusters on chromosome 18. Alternative splicing of this gene results in multiple transcript variants. At least one of these variants encodes a preproprotein that is proteolytically processed to generate the mature protein. [provided by RefSeq, Nov 2015]

DSCAS (HGNC:51116): (DSC1/DSC2 antisense RNA)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024421.2. 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
	DSC1	NM_024421.2	MANE Select	c.2611G>A	p.Glu871Lys	missense	Exon 16 of 16	NP_077739.1	Q08554-1
	DSC1	NM_004948.3		c.*134G>A		3_prime_UTR	Exon 17 of 17	NP_004939.1	Q08554-2
	DSCAS	NR_110785.1		n.209-20211C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC1	ENST00000257198.6	TSL:2 MANE Select	c.2611G>A	p.Glu871Lys	missense	Exon 16 of 16	ENSP00000257198.6	Q08554-1
	DSC1	ENST00000257197.7	TSL:1	c.*134G>A		3_prime_UTR	Exon 17 of 17	ENSP00000257197.3	Q08554-2
	DSCAS	ENST00000654403.3		n.283C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.1
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.35
MutPred		0.53		Gain of ubiquitination at E871 (P = 0.0077)
MVP		0.94
MPC		0.41
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.80
gMVP		0.35
Mutation Taster		=66/34	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: rs781222904; hg19: chr18-28710551;