15-48134912-TCAGAGACTGTG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_205850.3(SLC24A5):c.522_532del(p.Arg174SerfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,074 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SLC24A5 NM_205850.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.27

Genes affected

SLC24A5 (HGNC:20611): (solute carrier family 24 member 5) This gene is a member of the potassium-dependent sodium/calcium exchanger family and encodes an intracellular membrane protein with 2 large hydrophilic loops and 2 sets of multiple transmembrane-spanning segments. Sequence variation in this gene has been associated with differences in skin pigmentation. [provided by RefSeq, Jul 2008]

MYEF2 (HGNC:17940): (myelin expression factor 2) Enables RNA binding activity. Involved in myotube differentiation and neuron differentiation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48134912-TCAGAGACTGTG-T is Pathogenic according to our data. Variant chr15-48134912-TCAGAGACTGTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 1939262.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC24A5	NM_205850.3	c.522_532del	p.Arg174SerfsTer5	frameshift_variant	5/9	ENST00000341459.8
MYEF2	NM_016132.5	c.*7985_*7995del		3_prime_UTR_variant	17/17	ENST00000324324.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC24A5	ENST00000341459.8	c.522_532del	p.Arg174SerfsTer5	frameshift_variant	5/9	1	NM_205850.3	P1
SLC24A5	ENST00000449382.2	c.342_352del	p.Arg114SerfsTer5	frameshift_variant	4/8	1
MYEF2	ENST00000324324.12	c.*7985_*7995del		3_prime_UTR_variant	17/17	1	NM_016132.5	P4
SLC24A5	ENST00000463289.1	n.282_292del		non_coding_transcript_exon_variant	4/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460074 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 726188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 02, 2022

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with SLC24A5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg174Serfs*5) in the SLC24A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC24A5 are known to be pathogenic (PMID: 23985994, 26686029). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-48427109;