rs17881440

Variant names:

• chr11-65182905-G-C
• rs17881440
• NM_005186.4:c.204G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005186.4(CAPN1):​c.204G>C​(p.Leu68Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,610,132 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (15 hom.)
• Consequence: CAPN1 NM_005186.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.13
• Publications: 1 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.021).
• BP6: Variant 11-65182905-G-C is Benign according to our data. Variant chr11-65182905-G-C is described in ClinVar as Benign. ClinVar VariationId is 781962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00108 (164/152296) while in subpopulation SAS AF = 0.00994 (48/4830). AF 95% confidence interval is 0.0077. There are 2 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.204G>C	p.Leu68Leu	synonymous	Exon 2 of 22	NP_005177.2
	CAPN1	NM_001198868.2		c.204G>C	p.Leu68Leu	synonymous	Exon 2 of 22	NP_001185797.1	P07384
	CAPN1	NM_001198869.2		c.204G>C	p.Leu68Leu	synonymous	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.204G>C	p.Leu68Leu	synonymous	Exon 2 of 22	ENSP00000279247.7	P07384
	CAPN1	ENST00000524773.5	TSL:1	c.204G>C	p.Leu68Leu	synonymous	Exon 2 of 22	ENSP00000434176.1	P07384
	CAPN1	ENST00000527323.5	TSL:1	c.204G>C	p.Leu68Leu	synonymous	Exon 1 of 21	ENSP00000431984.1	P07384

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152178 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00259 AC: 624 AN: 240732 AF XY: 0.00306

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00260

Gnomad NFE exome AF: 0.000680

Gnomad OTH exome AF: 0.00204

GnomAD4 exome AF: 0.00138 AC: 2015 AN: 1457836 Hom.: 15 Cov.: 31 AF XY: 0.00175 AC XY: 1269 AN XY: 724884

African (AFR) AF: 0.0000899 AC: 3 AN: 33374

American (AMR) AF: 0.000136 AC: 6 AN: 43996

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 326 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39534

South Asian (SAS) AF: 0.0115 AC: 980 AN: 85508

European-Finnish (FIN) AF: 0.00316 AC: 168 AN: 53168

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5758

European-Non Finnish (NFE) AF: 0.000338 AC: 375 AN: 1110260

Other (OTH) AF: 0.00229 AC: 138 AN: 60236

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152296 Hom.: 2 Cov.: 33 AF XY: 0.00117 AC XY: 87 AN XY: 74470

African (AFR) AF: 0.000120 AC: 5 AN: 41558

American (AMR) AF: 0.000131 AC: 2 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00994 AC: 48 AN: 4830

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.000733

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.7
DANN	Benign	0.57
PhyloP100		1.1
PromoterAI		0.016	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17881440; hg19: chr11-64950376;