19-1036169-G-C

Variant names:

• chr19-1036169-G-C
• rs201618086
• NM_004368.4:c.430G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004368.4(CNN2):​c.430G>C​(p.Val144Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. V144I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: CNN2 NM_004368.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31619865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNN2	NM_004368.4	c.430G>C	p.Val144Leu	missense_variant	Exon 5 of 7	ENST00000263097.9	NP_004359.1
CNN2	NM_001303501.2	c.493G>C	p.Val165Leu	missense_variant	Exon 5 of 7		NP_001290430.1
CNN2	NM_001303499.2	c.397G>C	p.Val133Leu	missense_variant	Exon 5 of 7		NP_001290428.1
CNN2	NM_201277.3	c.391-247G>C		intron_variant	Intron 4 of 5		NP_958434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNN2	ENST00000263097.9	c.430G>C	p.Val144Leu	missense_variant	Exon 5 of 7	1	NM_004368.4	ENSP00000263097.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32

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

GnomAD4 exome Cov.: 34

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	0.0095	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;T;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T;T;T;T;T;.
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.32	T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	L;.;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.0	N;N;N;.;.;N
REVEL	Benign	0.17
Sift	Benign	0.064	T;T;T;.;.;T
Sift4G	Benign	0.26	T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;.;.
Vest4		0.63
MutPred		0.29		.;.;Loss of methylation at K166 (P = 0.0354);.;.;.;
MVP		0.62
MPC		0.097
ClinPred		0.75	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.74

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

LitVar

Other links and lift over

dbSNP: rs201618086; hg19: chr19-1036168;