12-54644751-C-T

Variant names:

• chr12-54644751-C-T
• rs199541255
• NM_053283.4:c.295G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_053283.4(DCD):​c.295G>A​(p.Val99Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000318 in 1,604,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: DCD NM_053283.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0720

Genes affected

DCD (HGNC:14669): (dermcidin) This antimicrobial gene encodes a secreted protein that is subsequently processed into mature peptides of distinct biological activities. The C-terminal peptide is constitutively expressed in sweat and has antibacterial and antifungal activities. The N-terminal peptide, also known as diffusible survival evasion peptide, promotes neural cell survival under conditions of severe oxidative stress. A glycosylated form of the N-terminal peptide may be associated with cachexia (muscle wasting) in cancer patients. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039604962).
• BP6: Variant 12-54644751-C-T is Benign according to our data. Variant chr12-54644751-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2331765.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCD	NM_053283.4	c.295G>A	p.Val99Ile	missense_variant	Exon 5 of 5	ENST00000293371.11	NP_444513.1
DCD	NM_001300854.2	c.359G>A	p.Arg120His	missense_variant	Exon 6 of 6		NP_001287783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCD	ENST00000293371.11	c.295G>A	p.Val99Ile	missense_variant	Exon 5 of 5	1	NM_053283.4	ENSP00000293371.6
DCD	ENST00000456047.2	c.359G>A	p.Arg120His	missense_variant	Exon 6 of 6	1		ENSP00000406773.2
DCD	ENST00000546807.5	n.*228G>A		non_coding_transcript_exon_variant	Exon 6 of 6	1		ENSP00000450415.1
DCD	ENST00000546807.5	n.*228G>A		3_prime_UTR_variant	Exon 6 of 6	1		ENSP00000450415.1

Frequencies

GnomAD3 genomes AF: 0.0000402 AC: 6 AN: 149240 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000670

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000591

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000626 AC: 15 AN: 239750 Hom.: 0 AF XY: 0.0000773 AC XY: 10 AN XY: 129372

Gnomad AFR exome AF: 0.0000663

Gnomad AMR exome AF: 0.000207

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000555

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000562

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000309 AC: 45 AN: 1455044 Hom.: 0 Cov.: 33 AF XY: 0.0000387 AC XY: 28 AN XY: 723250

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000181

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000190

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000402 AC: 6 AN: 149350 Hom.: 0 Cov.: 29 AF XY: 0.0000413 AC XY: 3 AN XY: 72706

Gnomad4 AFR AF: 0.0000249

Gnomad4 AMR AF: 0.0000669

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000591

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000345 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 10, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.32
DANN	Benign	0.41
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.000080	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.050
Sift	Pathogenic	0.0	D
Vest4		0.059
MVP		0.11
ClinPred		0.0067	T
GERP RS		-1.8
gMVP		0.0048

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199541255; hg19: chr12-55038535;