chr19-38731075-CCCATGCCCCA-C

Variant names:

• chr19-38731075-CCCATGCCCCA-C
• rs141208726
• NM_004924.6:c.*1651_*1660delCCACCATGCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004924.6(ACTN4):​c.*1651_*1660delCCACCATGCC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,587,832 control chromosomes in the GnomAD database, including 25,083 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2053 hom., cov: 29)
  • Exomes 𝑓: 0.17 (23030 hom.)
• Consequence: ACTN4 NM_004924.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.154
• Publications: 1 publications found

Genes affected

ACTN4 (HGNC:166): (actinin alpha 4) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, alpha actinin isoform which is concentrated in the cytoplasm, and thought to be involved in metastatic processes. Mutations in this gene have been associated with focal and segmental glomerulosclerosis. [provided by RefSeq, Jul 2008]

CAPN12 (HGNC:13249): (calpain 12) 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 a member of the calpain large subunit family. [provided by RefSeq, Jun 2012]

CAPN12 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AR Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 19-38731075-CCCATGCCCCA-C is Benign according to our data. Variant chr19-38731075-CCCATGCCCCA-C is described in ClinVar as Benign. ClinVar VariationId is 1293786.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004924.6. 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
	ACTN4	NM_004924.6	MANE Select	c.*1651_*1660delCCACCATGCC		3_prime_UTR	Exon 21 of 21	NP_004915.2
	CAPN12	NM_144691.4	MANE Select	c.2074+22_2074+31delTGGGGCATGG		intron	N/A	NP_653292.2	Q6ZSI9
	ACTN4	NM_001411143.1		c.*1651_*1660delCCACCATGCC		3_prime_UTR	Exon 21 of 21	NP_001398072.1	F5GXS2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.*1651_*1660delCCACCATGCC		3_prime_UTR	Exon 21 of 21	ENSP00000252699.2	O43707-1
	CAPN12	ENST00000328867.9	TSL:1 MANE Select	c.2074+22_2074+31delTGGGGCATGG		intron	N/A	ENSP00000331636.3	Q6ZSI9
	CAPN12	ENST00000593700.5	TSL:1	n.638+22_638+31delTGGGGCATGG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23196 AN: 151948 Hom.: 2052 Cov.: 29

Gnomad AFR AF: 0.0863

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.00829

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.174 AC: 35906 AN: 206704 AF XY: 0.180

Gnomad AFR exome AF: 0.0994

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.225

Gnomad EAS exome AF: 0.00418

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.175 AC: 251212 AN: 1435766 Hom.: 23030 AF XY: 0.177 AC XY: 125869 AN XY: 712110

African (AFR) AF: 0.0877 AC: 2889 AN: 32952

American (AMR) AF: 0.120 AC: 4905 AN: 40918

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 5620 AN: 25630

East Asian (EAS) AF: 0.00233 AC: 89 AN: 38170

South Asian (SAS) AF: 0.167 AC: 13870 AN: 82966

European-Finnish (FIN) AF: 0.168 AC: 8420 AN: 50172

Middle Eastern (MID) AF: 0.334 AC: 1857 AN: 5558

European-Non Finnish (NFE) AF: 0.185 AC: 203452 AN: 1100090

Other (OTH) AF: 0.170 AC: 10110 AN: 59310

GnomAD4 genome AF: 0.153 AC: 23205 AN: 152066 Hom.: 2053 Cov.: 29 AF XY: 0.151 AC XY: 11233 AN XY: 74334

African (AFR) AF: 0.0863 AC: 3583 AN: 41494

American (AMR) AF: 0.161 AC: 2459 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 753 AN: 3472

East Asian (EAS) AF: 0.00830 AC: 43 AN: 5178

South Asian (SAS) AF: 0.158 AC: 761 AN: 4810

European-Finnish (FIN) AF: 0.160 AC: 1689 AN: 10588

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.193 AC: 13106 AN: 67936

Other (OTH) AF: 0.186 AC: 392 AN: 2106

Alfa AF: 0.180 Hom.: 429

Bravo AF: 0.149

Asia WGS AF: 0.0830 AC: 288 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141208726; hg19: chr19-39221715;