chr2-96829045-A-G

Variant names:

• chr2-96829045-A-G
• rs758128177
• NM_017623.5:c.1970A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_017623.5(CNNM3):​c.1970A>G​(p.Asn657Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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: 6.8e-7 (0 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.647
• 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]

ANKRD23 (HGNC:24470): (ankyrin repeat domain 23) This gene is a member of the muscle ankyrin repeat protein (MARP) family and encodes a protein with four tandem ankyrin-like repeats. The protein is localized to the nucleus, functioning as a transcriptional regulator. Expression of this protein is induced during recovery following starvation. [provided by RefSeq, Jul 2008]

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.019532174).
• BP6: Variant 2-96829045-A-G is Benign according to our data. Variant chr2-96829045-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3834545.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.1970A>G	p.Asn657Ser	missense	Exon 7 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.1826A>G	p.Asn609Ser	missense	Exon 6 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.1970A>G	p.Asn657Ser	missense	Exon 7 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000465224.5	TSL:1	n.1492A>G		non_coding_transcript_exon	Exon 3 of 4
	CNNM3	ENST00000947263.1		c.1955A>G	p.Asn652Ser	missense	Exon 7 of 8	ENSP00000617322.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250804 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461592 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727112

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60368

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	0.064
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.3
DANN	Benign	0.73
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.47	N
PhyloP100		0.65
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.030
MutPred		0.24		Loss of catalytic residue at N657 (P = 0.0058)
MVP		0.10
ClinPred		0.019	T
GERP RS		-0.53
Varity_R		0.054
gMVP		0.11
Mutation Taster		=99/1	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: rs758128177; hg19: chr2-97494782;