17-41974115-G-T

Variant names:

• chr17-41974115-G-T
• rs11079028
• NM_033133.5:c.*191G>T

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.*191G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000032 in 312,484 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: 30)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: CNP NM_033133.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.605
• Publications: 18 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=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNP	NM_033133.5	c.*191G>T		3_prime_UTR_variant	Exon 4 of 4	ENST00000393892.8	NP_149124.3
CNP	NM_001330216.2	c.*191G>T		3_prime_UTR_variant	Exon 4 of 4		NP_001317145.1
CNP	XM_011524340.3	c.*191G>T		3_prime_UTR_variant	Exon 4 of 4		XP_011522642.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNP	ENST00000393892.8	c.*191G>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_033133.5	ENSP00000377470.2
CNP	ENST00000393888.1	c.*191G>T		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000377466.1
CNP	ENST00000472031.1	c.*634G>T		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000467641.1
CNP	ENST00000486438.1	n.*153G>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000320 AC: 1 AN: 312484 Hom.: 0 Cov.: 5 AF XY: 0.00000632 AC XY: 1 AN XY: 158198

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 8382

American (AMR) AF: 0.00 AC: 0 AN: 9028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9798

East Asian (EAS) AF: 0.00 AC: 0 AN: 22114

South Asian (SAS) AF: 0.00 AC: 0 AN: 11654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1430

European-Non Finnish (NFE) AF: 0.00000471 AC: 1 AN: 212130

Other (OTH) AF: 0.00 AC: 0 AN: 18218

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 3750

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.7
DANN	Benign	0.55
PhyloP100		0.60
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.1

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

Other links and lift over

dbSNP: rs11079028; hg19: chr17-40126133;