2-96799118-C-G

Variant names:

• chr2-96799118-C-G
• rs1432600424
• NM_020184.4:c.1743C>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_020184.4(CNNM4):​c.1743C>G​(p.Tyr581*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y581Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNNM4 NM_020184.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.196
• Publications: 1 publications found

Genes affected

CNNM4 (HGNC:105): (cyclin and CBS domain divalent metal cation transport mediator 4) This gene encodes a member of the ancient conserved domain containing protein family. Members of this protein family contain a cyclin box motif and have structural similarity to the cyclins. The encoded protein may play a role in metal ion transport. Mutations in this gene are associated with Jalili syndrome which consists of cone-rod dystrophy and amelogenesis imperfecta. [provided by RefSeq, Feb 2010]

CNNM4 Gene-Disease associations (from GenCC):

• Jalili syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-96799118-C-G is Pathogenic according to our data. Variant chr2-96799118-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 518456.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM4	NM_020184.4	c.1743C>G	p.Tyr581*	stop_gained	Exon 4 of 7	ENST00000377075.3	NP_064569.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM4	ENST00000377075.3	c.1743C>G	p.Tyr581*	stop_gained	Exon 4 of 7	1	NM_020184.4	ENSP00000366275.2
CNNM4	ENST00000493384.1	n.523C>G		non_coding_transcript_exon_variant	Exon 4 of 4	4
CNNM4	ENST00000496186.5	n.417C>G		non_coding_transcript_exon_variant	Exon 4 of 6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Jalili syndrome Pathogenic:1

-

Piracicaba Dental School, University of Campinas

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jalili syndrome (JS) is an autosomal recessive disease characterized by a combination of cone-rode retinal dytrophy (CRD) and amelogenesis imperfect (AI). Mutations in cyclin and CBS domain divalent metal cation transport mediator 4 (CNNM4) gene cause JS. The syndrome showed variable clinical expressivity, suggesting that the mutant protein carrying the compound variants is partially active inducing a variable and less severe phenotype. Together the mutation c.1743C>G (p.Y581*), we found the missense mutation c.971T>C (p.L324P) in heterozygosis in the affected patients. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		0.20
Vest4		0.26
GERP RS		5.0
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1432600424; hg19: chr2-97464855;