chr19-1037767-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2 PP5

The NM_004368.4(CNN2):​c.797G>A​(p.Arg266Gln) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.051 (0 hom., cov: 36)
  • Exomes 𝑓: 0.00011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNN2 NM_004368.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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: Uncertain_significance. The variant received 2 ACMG points.

• 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).
• PP5: Variant 19-1037767-G-A is Pathogenic according to our data. 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.

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>A	p.Arg266Gln	missense	Exon 7 of 7	NP_004359.1	Q99439-1
	CNN2	NM_001303501.2		c.860G>A	p.Arg287Gln	missense	Exon 7 of 7	NP_001290430.1	B4DUT8
	CNN2	NM_001303499.2		c.764G>A	p.Arg255Gln	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>A	p.Arg266Gln	missense	Exon 7 of 7	ENSP00000263097.2	Q99439-1
	CNN2	ENST00000562958.6	TSL:2	c.860G>A	p.Arg287Gln	missense	Exon 7 of 7	ENSP00000456436.1	B4DUT8
	CNN2	ENST00000926772.1		c.791G>A	p.Arg264Gln	missense	Exon 7 of 7	ENSP00000596831.1

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 4035 AN: 78982 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.0736

Gnomad AMI AF: 0.0616

Gnomad AMR AF: 0.0393

Gnomad ASJ AF: 0.0304

Gnomad EAS AF: 0.0429

Gnomad SAS AF: 0.0430

Gnomad FIN AF: 0.0682

Gnomad MID AF: 0.0236

Gnomad NFE AF: 0.0410

Gnomad OTH AF: 0.0469

GnomAD2 exomes AF: 0.0000846 AC: 21 AN: 248214 AF XY: 0.0000518

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000109 AC: 156 AN: 1427600 Hom.: 0 Cov.: 34 AF XY: 0.000156 AC XY: 110 AN XY: 706142

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000304 AC: 1 AN: 32890

American (AMR) AF: 0.000324 AC: 14 AN: 43226

Ashkenazi Jewish (ASJ) AF: 0.000155 AC: 4 AN: 25814

East Asian (EAS) AF: 0.000210 AC: 8 AN: 38122

South Asian (SAS) AF: 0.00 AC: 0 AN: 83478

European-Finnish (FIN) AF: 0.000390 AC: 19 AN: 48710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4190

European-Non Finnish (NFE) AF: 0.0000980 AC: 107 AN: 1092368

Other (OTH) AF: 0.0000510 AC: 3 AN: 58802

⚠️ 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 Data not reliable, filtered out with message: InbreedingCoeff AF: 0.0511 AC: 4040 AN: 79012 Hom.: 0 Cov.: 36 AF XY: 0.0562 AC XY: 2146 AN XY: 38184

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0735 AC: 1474 AN: 20068

American (AMR) AF: 0.0392 AC: 332 AN: 8462

Ashkenazi Jewish (ASJ) AF: 0.0304 AC: 57 AN: 1876

East Asian (EAS) AF: 0.0430 AC: 128 AN: 2974

South Asian (SAS) AF: 0.0434 AC: 118 AN: 2718

European-Finnish (FIN) AF: 0.0682 AC: 388 AN: 5686

Middle Eastern (MID) AF: 0.0255 AC: 5 AN: 196

European-Non Finnish (NFE) AF: 0.0411 AC: 1454 AN: 35412

Other (OTH) AF: 0.0484 AC: 58 AN: 1198

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.204 Hom.: 0

ExAC AF: 0.000222 AC: 27

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Pulmonary artery atresia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.15	T
Polyphen		0.28	B
Vest4		0.50
MVP		0.92
MPC		0.14
ClinPred		0.15	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.62
Mutation Taster		=58/42	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: rs78386506; hg19: chr19-1037766; COSMIC: COSV54023585; COSMIC: COSV54023585;