19-38731075-CCCATGCCCCA-CCCATGCCCCACCATGCCCCA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004924.6(ACTN4):​c.*1651_*1660dupCCACCATGCC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,435,918 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACTN4 NM_004924.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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_*1660dupCCACCATGCC		3_prime_UTR	Exon 21 of 21	NP_004915.2
	CAPN12	NM_144691.4	MANE Select	c.2074+22_2074+31dupTGGGGCATGG		intron	N/A	NP_653292.2	Q6ZSI9
	ACTN4	NM_001411143.1		c.*1651_*1660dupCCACCATGCC		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_*1660dupCCACCATGCC		3_prime_UTR	Exon 21 of 21	ENSP00000252699.2	O43707-1
	CAPN12	ENST00000328867.9	TSL:1 MANE Select	c.2074+22_2074+31dupTGGGGCATGG		intron	N/A	ENSP00000331636.3	Q6ZSI9
	CAPN12	ENST00000593700.5	TSL:1	n.638+22_638+31dupTGGGGCATGG		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000484 AC: 1 AN: 206704 AF XY: 0.00000891

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1435918 Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1 AN XY: 712202

African (AFR) AF: 0.00 AC: 0 AN: 32954

American (AMR) AF: 0.00 AC: 0 AN: 40926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25630

East Asian (EAS) AF: 0.00 AC: 0 AN: 38170

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 82974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100206

Other (OTH) AF: 0.00 AC: 0 AN: 59320

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15

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;