NM_004368.4:c.493G>A

Variant names:

• chr19-1036232-G-A
• rs370563052
• NM_004368.4:c.493G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004368.4(CNN2):​c.493G>A​(p.Val165Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,594,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CNN2 NM_004368.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.61
• Publications: 0 publications found

Genes affected

CNN2 (HGNC:2156): (calponin 2) The protein encoded by this gene, which can bind actin, calmodulin, troponin C, and tropomyosin, may function in the structural organization of actin filaments. The encoded protein could play a role in smooth muscle contraction and cell adhesion. Several pseudogenes of this gene have been identified, and are present on chromosomes 1, 2, 3, 6, 9, 11, 13, 15, 16, 21 and 22. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.15171 (below the threshold of 3.09). Trascript score misZ: 0.22112 (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.20236751).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004368.4. 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
	CNN2	NM_004368.4	MANE Select	c.493G>A	p.Val165Ile	missense	Exon 5 of 7	NP_004359.1	Q99439-1
	CNN2	NM_001303501.2		c.556G>A	p.Val186Ile	missense	Exon 5 of 7	NP_001290430.1	B4DUT8
	CNN2	NM_001303499.2		c.460G>A	p.Val154Ile	missense	Exon 5 of 7	NP_001290428.1	B4DDF4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNN2	ENST00000263097.9	TSL:1 MANE Select	c.493G>A	p.Val165Ile	missense	Exon 5 of 7	ENSP00000263097.2	Q99439-1
	CNN2	ENST00000607102.1	TSL:1	c.34-184G>A		intron	N/A	ENSP00000475175.1	U3KPS3
	CNN2	ENST00000562958.6	TSL:2	c.556G>A	p.Val186Ile	missense	Exon 5 of 7	ENSP00000456436.1	B4DUT8

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000218 AC: 5 AN: 229732 AF XY: 0.0000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000289

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 25 AN: 1442540 Hom.: 0 Cov.: 34 AF XY: 0.0000210 AC XY: 15 AN XY: 715552

African (AFR) AF: 0.00 AC: 0 AN: 33060

American (AMR) AF: 0.00 AC: 0 AN: 42922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24802

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39514

South Asian (SAS) AF: 0.0000480 AC: 4 AN: 83362

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5092

European-Non Finnish (NFE) AF: 0.0000172 AC: 19 AN: 1101684

Other (OTH) AF: 0.00 AC: 0 AN: 59496

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.076
BayesDel_addAF	Benign	0.0076	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.012
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PhyloP100		9.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.20
Sift	Benign	0.53	T
Sift4G	Benign	0.73	T
Polyphen		0.23	B
Vest4		0.59
MVP		0.50
MPC		0.081
ClinPred		0.30	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.44
Mutation Taster		=66/34	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: rs370563052; hg19: chr19-1036231; COSMIC: COSV54037230; COSMIC: COSV54037230;