chr6-7542052-G-C

Variant names:

• chr6-7542052-G-C
• rs140403872
• NM_004415.4:c.137G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004415.4(DSP):​c.137G>C​(p.Gly46Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G46D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.126
• Publications: 1 publications found

Genes affected

DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

DSP-AS1 (HGNC:56039): (DSP antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02894634).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004415.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	NM_004415.4	MANE Select	c.137G>C	p.Gly46Ala	missense	Exon 1 of 24	NP_004406.2
	DSP	NM_001319034.2		c.137G>C	p.Gly46Ala	missense	Exon 1 of 24	NP_001305963.1
	DSP	NM_001008844.3		c.137G>C	p.Gly46Ala	missense	Exon 1 of 24	NP_001008844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	ENST00000379802.8	TSL:1 MANE Select	c.137G>C	p.Gly46Ala	missense	Exon 1 of 24	ENSP00000369129.3
	DSP	ENST00000418664.3	TSL:1	c.137G>C	p.Gly46Ala	missense	Exon 1 of 24	ENSP00000396591.2
	DSP	ENST00000710359.2		c.137G>C	p.Gly46Ala	missense	Exon 1 of 24	ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.1
DANN	Benign	0.74
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.13
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.048
Sift	Benign	1.0	T
Sift4G	Benign	0.87	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.17		Loss of disorder (P = 0.0786)
MVP		0.26
MPC		0.23
ClinPred		0.038	T
GERP RS		0.72
PromoterAI		-0.022	Neutral
Varity_R		0.073
gMVP		0.38
Mutation Taster		=97/3	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: rs140403872; hg19: chr6-7542285;