10-99330348-A-G

Position:

• chr10-99330348-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020348.3(CNNM1):​c.961A>G​(p.Ile321Val) variant causes a missense 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNNM1 NM_020348.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.310

Genes affected

CNNM1 (HGNC:102): (cyclin and CBS domain divalent metal cation transport mediator 1) This gene encodes a member of the ancient conserved domain protein family. The encoded protein may bind copper. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

CNNM1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051266074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNNM1	NM_020348.3	c.961A>G	p.Ile321Val	missense_variant	1/11	ENST00000356713.5	NP_065081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNNM1	ENST00000356713.5	c.961A>G	p.Ile321Val	missense_variant	1/11	1	NM_020348.3	ENSP00000349147.4
CNNM1	ENST00000696687.1	c.961A>G	p.Ile321Val	missense_variant	1/12			ENSP00000512809.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.90e-7 AC: 1 AN: 1449238 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 719440

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2023

The c.961A>G (p.I321V) alteration is located in exon 1 (coding exon 1) of the CNNM1 gene. This alteration results from a A to G substitution at nucleotide position 961, causing the isoleucine (I) at amino acid position 321 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.5
DANN	Benign	0.80
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-0.20	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.24
Sift	Benign	0.34	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.028
MutPred		0.44		Gain of catalytic residue at I321 (P = 0.0335);
MVP		0.068
ClinPred		0.19	T
GERP RS		-0.16
Varity_R		0.041
gMVP		0.14

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-101090105;