rs1432600424

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-96799118-C-G
• chr2-96799118-C-T
• chr2-96799118-C-A

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: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020184.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

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

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM4	ENST00000377075.3	TSL:1 MANE Select	c.1743C>G	p.Tyr581*	stop_gained	Exon 4 of 7	ENSP00000366275.2	Q6P4Q7-1
	CNNM4	ENST00000930282.1		c.1845C>G	p.Tyr615*	stop_gained	Exon 4 of 7	ENSP00000600341.1
	CNNM4	ENST00000966765.1		c.1743C>G	p.Tyr581*	stop_gained	Exon 4 of 8	ENSP00000636824.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Jalili syndrome (1)

Computational scores

Source: dbNSFP v4.9

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;