2-96761059-C-A

Variant names:

• chr2-96761059-C-A
• NM_020184.4:c.60C>A
• CNNM4 p.Leu20Leu

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_020184.4(CNNM4):​c.60C>A​(p.Leu20Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L20L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CNNM4 NM_020184.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.612
• 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP7: Synonymous conserved (PhyloP=0.612 with no splicing effect.

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.60C>A	p.Leu20Leu	synonymous	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.60C>A	p.Leu20Leu	synonymous	Exon 1 of 7	ENSP00000366275.2	Q6P4Q7-1
	CNNM4	ENST00000930282.1		c.60C>A	p.Leu20Leu	synonymous	Exon 1 of 7	ENSP00000600341.1
	CNNM4	ENST00000966765.1		c.60C>A	p.Leu20Leu	synonymous	Exon 1 of 8	ENSP00000636824.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	10
DANN	Benign	0.66
PhyloP100		0.61
PromoterAI		-0.26	Neutral
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-97426796;