rs138005500

Variant names:

• chr2-240587011-C-G
• rs138005500
• NM_023083.4:c.100C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-240587011-C-G
• chr2-240587011-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_023083.4(CAPN10):​c.100C>G​(p.Leu34Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.008 in 1,475,758 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (56 hom.)
• Consequence: CAPN10 NM_023083.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.15
• Publications: 10 publications found

Genes affected

CAPN10 (HGNC:1477): (calpain 10) Calpains represent a ubiquitous, well-conserved family of calcium-dependent cysteine proteases. The calpain proteins are heterodimers consisting of an invariant small subunit and variable large subunits. The large catalytic subunit has four domains: domain I, the N-terminal regulatory domain that is processed upon calpain activation; domain II, the protease domain; domain III, a linker domain of unknown function; and domain IV, the calmodulin-like calcium-binding domain. This gene encodes a large subunit. It is an atypical calpain in that it lacks the calmodulin-like calcium-binding domain and instead has a divergent C-terminal domain. It is similar in organization to calpains 5 and 6. This gene is associated with type 2 or non-insulin-dependent diabetes mellitus (NIDDM), and is located within the NIDDM1 region. Multiple alternative transcript variants have been described for this gene. [provided by RefSeq, Sep 2010]

CAPN10 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049797).
• BP6: Variant 2-240587011-C-G is Benign according to our data. Variant chr2-240587011-C-G is described in ClinVar as Benign. ClinVar VariationId is 716765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023083.4. 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
	CAPN10	NM_023083.4	MANE Select	c.100C>G	p.Leu34Val	missense	Exon 1 of 12	NP_075571.2	Q9HC96-1
	CAPN10	NM_023085.4		c.100C>G	p.Leu34Val	missense	Exon 1 of 10	NP_075573.3	Q9HC96-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN10	ENST00000391984.7	TSL:1 MANE Select	c.100C>G	p.Leu34Val	missense	Exon 1 of 12	ENSP00000375844.2	Q9HC96-1
	CAPN10	ENST00000354082.8	TSL:1	c.100C>G	p.Leu34Val	missense	Exon 1 of 10	ENSP00000270362.6	Q9HC96-3
	CAPN10	ENST00000352879.8	TSL:1	c.100C>G	p.Leu34Val	missense	Exon 1 of 4	ENSP00000289381.6	Q9HC96-8

Frequencies

GnomAD3 genomes AF: 0.00801 AC: 1219 AN: 152254 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.0292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00807 AC: 730 AN: 90404 AF XY: 0.00739

Gnomad AFR exome AF: 0.00151

Gnomad AMR exome AF: 0.00329

Gnomad ASJ exome AF: 0.00757

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0209

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00508

GnomAD4 exome AF: 0.00800 AC: 10593 AN: 1323390 Hom.: 56 Cov.: 31 AF XY: 0.00777 AC XY: 5070 AN XY: 652202

African (AFR) AF: 0.00115 AC: 31 AN: 26990

American (AMR) AF: 0.00362 AC: 94 AN: 25974

Ashkenazi Jewish (ASJ) AF: 0.00748 AC: 175 AN: 23394

East Asian (EAS) AF: 0.0000354 AC: 1 AN: 28288

South Asian (SAS) AF: 0.000251 AC: 18 AN: 71780

European-Finnish (FIN) AF: 0.0226 AC: 1019 AN: 45000

Middle Eastern (MID) AF: 0.000400 AC: 2 AN: 4996

European-Non Finnish (NFE) AF: 0.00857 AC: 8940 AN: 1042580

Other (OTH) AF: 0.00575 AC: 313 AN: 54388

GnomAD4 genome AF: 0.00799 AC: 1217 AN: 152368 Hom.: 15 Cov.: 33 AF XY: 0.00886 AC XY: 660 AN XY: 74520

African (AFR) AF: 0.00168 AC: 70 AN: 41584

American (AMR) AF: 0.00372 AC: 57 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.0292 AC: 310 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0108 AC: 735 AN: 68030

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00940 Hom.: 3

Bravo AF: 0.00562

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.000982 AC: 4

ESP6500EA AF: 0.00568 AC: 46

ExAC AF: 0.00293 AC: 300

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.081
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.11
Sift	Benign	0.096	T
Sift4G	Benign	0.11	T
Polyphen		0.95	P
Vest4		0.15
MVP		0.66
MPC		0.56
ClinPred		0.018	T
GERP RS		2.5
PromoterAI		-0.024	Neutral
Varity_R		0.10
gMVP		0.26
Mutation Taster		=99/1	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: rs138005500; hg19: chr2-241526428; COSMIC: COSV54376248; COSMIC: COSV54376248;