17-41968753-T-A

Variant names:

• chr17-41968753-T-A
• rs8078650
• NM_033133.5:c.676+13T>A

Variant summary

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

The NM_033133.5(CNP):​c.676+13T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,445,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CNP NM_033133.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.677
• Publications: 0 publications found

Genes affected

CNP (HGNC:2158): (2',3'-cyclic nucleotide 3' phosphodiesterase) Predicted to enable 2',3'-cyclic-nucleotide 3'-phosphodiesterase activity. Involved in substantia nigra development. Located in several cellular components, including extracellular space; microtubule; and plasma membrane. Implicated in hypomyelinating leukodystrophy 20; multiple sclerosis; and schizophrenia. Biomarker of alcoholic liver cirrhosis; multiple sclerosis; and restless legs syndrome. [provided by Alliance of Genome Resources, Apr 2022]

CNP Gene-Disease associations (from GenCC):

• leukodystrophy, hypomyelinating, 20

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

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 (BayesDel_noAF=-0.85).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033133.5. 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
	CNP	NM_033133.5	MANE Select	c.676+13T>A		intron	N/A	NP_149124.3
	CNP	NM_001330216.2		c.616+13T>A		intron	N/A	NP_001317145.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNP	ENST00000393892.8	TSL:1 MANE Select	c.676+13T>A		intron	N/A	ENSP00000377470.2
	CNP	ENST00000393888.1	TSL:1	c.616+13T>A		intron	N/A	ENSP00000377466.1
	CNP	ENST00000472031.1	TSL:2	c.3+1866T>A		intron	N/A	ENSP00000467641.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1445364 Hom.: 0 Cov.: 32 AF XY: 0.00000418 AC XY: 3 AN XY: 717208

African (AFR) AF: 0.00 AC: 0 AN: 32838

American (AMR) AF: 0.00 AC: 0 AN: 42948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25236

East Asian (EAS) AF: 0.00 AC: 0 AN: 39374

South Asian (SAS) AF: 0.00 AC: 0 AN: 84686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1102490

Other (OTH) AF: 0.00 AC: 0 AN: 59546

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.1
DANN	Benign	0.22
PhyloP100		0.68
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8

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: rs8078650; hg19: chr17-40120771;