chr2-96816423-T-C

Variant names:

• chr2-96816423-T-C
• rs1424596436
• NM_017623.5:c.146T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_017623.5(CNNM3):​c.146T>C​(p.Val49Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000814 in 1,229,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.412
• Publications: 0 publications found

Genes affected

CNNM3 (HGNC:104): (cyclin and CBS domain divalent metal cation transport mediator 3) Predicted to enable transmembrane transporter activity. Predicted to be involved in ion transport; magnesium ion homeostasis; and transmembrane transport. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

CNNM3-DT (HGNC:53592): (CNNM3 divergent transcript)

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 (MetaRNN=0.13809648).
• BP6: Variant 2-96816423-T-C is Benign according to our data. Variant chr2-96816423-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2263302.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017623.5. 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
	CNNM3	NM_017623.5	MANE Select	c.146T>C	p.Val49Ala	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.146T>C	p.Val49Ala	missense	Exon 1 of 7	NP_951060.1	Q8NE01-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM3	ENST00000305510.4	TSL:1 MANE Select	c.146T>C	p.Val49Ala	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000947263.1		c.146T>C	p.Val49Ala	missense	Exon 1 of 8	ENSP00000617322.1
	CNNM3	ENST00000947265.1		c.146T>C	p.Val49Ala	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.14e-7 AC: 1 AN: 1229096 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 600888

⚠️ 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: 24460

American (AMR) AF: 0.00 AC: 0 AN: 12340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17602

East Asian (EAS) AF: 0.00 AC: 0 AN: 27640

South Asian (SAS) AF: 0.00 AC: 0 AN: 54090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36196

Middle Eastern (MID) AF: 0.000286 AC: 1 AN: 3500

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1003072

Other (OTH) AF: 0.00 AC: 0 AN: 50196

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.2
DANN	Benign	0.47
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.28	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.81	N
PhyloP100		0.41
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.19
Sift	Benign	0.68	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.047
MutPred		0.38		Gain of disorder (P = 0.0184)
MVP		0.055
ClinPred		0.068	T
GERP RS		-0.47
PromoterAI		-0.17	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4
Varity_R		0.031
gMVP		0.21
Mutation Taster		=92/8	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

Other links and lift over

dbSNP: rs1424596436; hg19: chr2-97482160;