19-1037767-G-T

Variant names:

• chr19-1037767-G-T
• rs78386506
• NM_004368.4:c.797G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Strong

The NM_004368.4(CNN2):​c.797G>T​(p.Arg266Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R266Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 36)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CNN2 NM_004368.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.53
• Publications: 15 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1037767-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1696851.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

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.797G>T	p.Arg266Leu	missense	Exon 7 of 7	NP_004359.1	Q99439-1
	CNN2	NM_001303501.2		c.860G>T	p.Arg287Leu	missense	Exon 7 of 7	NP_001290430.1	B4DUT8
	CNN2	NM_001303499.2		c.764G>T	p.Arg255Leu	missense	Exon 7 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.797G>T	p.Arg266Leu	missense	Exon 7 of 7	ENSP00000263097.2	Q99439-1
	CNN2	ENST00000562958.6	TSL:2	c.860G>T	p.Arg287Leu	missense	Exon 7 of 7	ENSP00000456436.1	B4DUT8
	CNN2	ENST00000926772.1		c.791G>T	p.Arg264Leu	missense	Exon 7 of 7	ENSP00000596831.1

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248214 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448286 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 719666

African (AFR) AF: 0.00 AC: 0 AN: 33198

American (AMR) AF: 0.00 AC: 0 AN: 44098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39154

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4252

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105756

Other (OTH) AF: 0.00 AC: 0 AN: 59702

GnomAD4 genome Cov.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.057	T
Polyphen		0.15	B
Vest4		0.85
MutPred		0.91		Gain of sheet (P = 0.0827)
MVP		0.94
MPC		0.19
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.72
Mutation Taster		=41/59	disease causing

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: rs78386506; hg19: chr19-1037766;