rs138515103

Variant names:

• chr19-1036205-G-A
• rs138515103
• NM_004368.4:c.466G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1036205-G-A
• chr19-1036205-G-C
• chr19-1036205-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_004368.4(CNN2):​c.466G>A​(p.Asp156Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 150,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (1 hom.)
  • Failed GnomAD Quality Control
• 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 2 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=0.37273848).

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.466G>A	p.Asp156Asn	missense	Exon 5 of 7	NP_004359.1	Q99439-1
	CNN2	NM_001303501.2		c.529G>A	p.Asp177Asn	missense	Exon 5 of 7	NP_001290430.1	B4DUT8
	CNN2	NM_001303499.2		c.433G>A	p.Asp145Asn	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.466G>A	p.Asp156Asn	missense	Exon 5 of 7	ENSP00000263097.2	Q99439-1
	CNN2	ENST00000607102.1	TSL:1	c.34-211G>A		intron	N/A	ENSP00000475175.1	U3KPS3
	CNN2	ENST00000562958.6	TSL:2	c.529G>A	p.Asp177Asn	missense	Exon 5 of 7	ENSP00000456436.1	B4DUT8

Frequencies

GnomAD3 genomes AF: 0.0000465 AC: 7 AN: 150566 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.000487

GnomAD2 exomes AF: 0.0000535 AC: 13 AN: 242812 AF XY: 0.0000534

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000902

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000819

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000864 AC: 1216 AN: 1406990 Hom.: 1 Cov.: 34 AF XY: 0.000883 AC XY: 614 AN XY: 695146

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

African (AFR) AF: 0.00235 AC: 74 AN: 31424

American (AMR) AF: 0.00979 AC: 337 AN: 34438

Ashkenazi Jewish (ASJ) AF: 0.00343 AC: 78 AN: 22754

East Asian (EAS) AF: 0.0000770 AC: 3 AN: 38958

South Asian (SAS) AF: 0.00340 AC: 262 AN: 76990

European-Finnish (FIN) AF: 0.000370 AC: 19 AN: 51416

Middle Eastern (MID) AF: 0.000802 AC: 4 AN: 4986

European-Non Finnish (NFE) AF: 0.000361 AC: 393 AN: 1088082

Other (OTH) AF: 0.000794 AC: 46 AN: 57942

⚠️ 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 AF: 0.0000465 AC: 7 AN: 150566 Hom.: 0 Cov.: 33 AF XY: 0.0000409 AC XY: 3 AN XY: 73418

African (AFR) AF: 0.00 AC: 0 AN: 40932

American (AMR) AF: 0.000199 AC: 3 AN: 15110

Ashkenazi Jewish (ASJ) AF: 0.000290 AC: 1 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67480

Other (OTH) AF: 0.000487 AC: 1 AN: 2054

Alfa AF: 0.0000663 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.11
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.27
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.045	D
Polyphen		0.92	P
Vest4		0.35
MVP		0.71
MPC		0.097
ClinPred		0.43	T
GERP RS		4.8
Varity_R		0.26
gMVP		0.44
Mutation Taster		=79/21	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: rs138515103; hg19: chr19-1036204; COSMIC: COSV54035352; COSMIC: COSV54035352;