rs776728125

Variant names:

• chr11-65182871-G-A
• rs776728125
• NM_005186.4:c.170G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-65182871-G-A
• chr11-65182871-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_005186.4(CAPN1):​c.170G>A​(p.Arg57His) variant causes a missense change. The variant allele was found at a frequency of 0.0000243 in 1,602,762 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: CAPN1 NM_005186.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.73
• Publications: 0 publications found

Genes affected

CAPN1 (HGNC:1476): (calpain 1) The calpains, calcium-activated neutral proteases, are nonlysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. The ubiquitous enzymes consist of heterodimers with distinct large, catalytic subunits associated with a common small, regulatory subunit. This gene encodes the large subunit of the ubiquitous enzyme, calpain 1. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

CAPN1 Gene-Disease associations (from GenCC):

• autosomal recessive spastic paraplegia type 76

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38993728).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005186.4. 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
	CAPN1	NM_005186.4	MANE Select	c.170G>A	p.Arg57His	missense	Exon 2 of 22	NP_005177.2
	CAPN1	NM_001198868.2		c.170G>A	p.Arg57His	missense	Exon 2 of 22	NP_001185797.1	P07384
	CAPN1	NM_001198869.2		c.170G>A	p.Arg57His	missense	Exon 2 of 22	NP_001185798.1	P07384

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN1	ENST00000279247.11	TSL:1 MANE Select	c.170G>A	p.Arg57His	missense	Exon 2 of 22	ENSP00000279247.7	P07384
	CAPN1	ENST00000524773.5	TSL:1	c.170G>A	p.Arg57His	missense	Exon 2 of 22	ENSP00000434176.1	P07384
	CAPN1	ENST00000527323.5	TSL:1	c.170G>A	p.Arg57His	missense	Exon 1 of 21	ENSP00000431984.1	P07384

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 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

GnomAD2 exomes AF: 0.0000395 AC: 9 AN: 227632 AF XY: 0.0000648

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: 0.0000195

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000262 AC: 38 AN: 1450626 Hom.: 0 Cov.: 31 AF XY: 0.0000291 AC XY: 21 AN XY: 720652

African (AFR) AF: 0.0000301 AC: 1 AN: 33186

American (AMR) AF: 0.00 AC: 0 AN: 42698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25834

East Asian (EAS) AF: 0.00 AC: 0 AN: 39114

South Asian (SAS) AF: 0.000214 AC: 18 AN: 84282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1107044

Other (OTH) AF: 0.0000667 AC: 4 AN: 60006

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74314

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

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ 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: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000579 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.0038
Eigen_PC	Benign	0.016
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.15
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.014	D
Polyphen		0.70	P
Vest4		0.35
MVP		0.99
MPC		0.84
ClinPred		0.50	D
GERP RS		3.3
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.45
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: rs776728125; hg19: chr11-64950342;