chr2-96761084-CT-C

Variant names:

• chr2-96761084-CT-C
• NM_020184.4:c.86delT

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.86delT​(p.Leu29ArgfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000227 in 1,318,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L29L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: CNNM4 NM_020184.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.341
• Publications: 0 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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 42 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-96761084-CT-C is Pathogenic according to our data. Variant chr2-96761084-CT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2013699.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.86delT	p.Leu29ArgfsTer21	frameshift	Exon 1 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.86delT	p.Leu29ArgfsTer21	frameshift	Exon 1 of 7	ENSP00000366275.2	Q6P4Q7-1
	CNNM4	ENST00000930282.1		c.86delT	p.Leu29ArgfsTer21	frameshift	Exon 1 of 7	ENSP00000600341.1
	CNNM4	ENST00000966765.1		c.86delT	p.Leu29ArgfsTer21	frameshift	Exon 1 of 8	ENSP00000636824.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000227 AC: 3 AN: 1318812 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 644032

African (AFR) AF: 0.00 AC: 0 AN: 29430

American (AMR) AF: 0.00 AC: 0 AN: 27698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19228

East Asian (EAS) AF: 0.00 AC: 0 AN: 35460

South Asian (SAS) AF: 0.00 AC: 0 AN: 63526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5086

European-Non Finnish (NFE) AF: 0.00000289 AC: 3 AN: 1039152

Other (OTH) AF: 0.00 AC: 0 AN: 53734

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34

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

hg19: chr2-97426821;