18-74583600-C-T

Variant names:

• chr18-74583600-C-T
• rs1244702565
• NM_032649.6:c.1349C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032649.6(CNDP1):​c.1349C>T​(p.Thr450Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CNDP1 NM_032649.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35

Genes affected

CNDP1 (HGNC:20675): (carnosine dipeptidase 1) This gene encodes a member of the M20 metalloprotease family. The encoded protein is specifically expressed in the brain, is a homodimeric dipeptidase which was identified as human carnosinase. This gene contains trinucleotide (CTG) repeat length polymorphism in the coding region. [provided by RefSeq, Jul 2008]

LOC124904324 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNDP1	NM_032649.6	c.1349C>T	p.Thr450Ile	missense_variant	Exon 11 of 12	ENST00000358821.8	NP_116038.4
LOC124904324	XR_007066415.1	n.78G>A		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNDP1	ENST00000358821.8	c.1349C>T	p.Thr450Ile	missense_variant	Exon 11 of 12	1	NM_032649.6	ENSP00000351682.3
CNDP1	ENST00000582365.1	c.1220C>T	p.Thr407Ile	missense_variant	Exon 10 of 11	5		ENSP00000462096.1
CNDP1	ENST00000582461.1	n.2230C>T		non_coding_transcript_exon_variant	Exon 3 of 3	5
CNDP1	ENST00000584004.5	n.873C>T		non_coding_transcript_exon_variant	Exon 6 of 7	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251458 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461820 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1349C>T (p.T450I) alteration is located in exon 11 (coding exon 11) of the CNDP1 gene. This alteration results from a C to T substitution at nucleotide position 1349, causing the threonine (T) at amino acid position 450 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	.;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	-0.23	T
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.9	D;.
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.86
MutPred		0.83		Gain of catalytic residue at P452 (P = 0.0424);.;
MVP		0.67
MPC		0.67
ClinPred		0.99	D
GERP RS		3.8
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1244702565; hg19: chr18-72250836;