2-44320424-CCC-TCT

Variant names:

• chr2-44320424-CCC-TCT
• NM_000341.4:c.1843_1845delCCCinsTCT
• SLC3A1 p.Pro615Ser

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_000341.4(SLC3A1):​c.1843_1845delCCCinsTCT​(p.Pro615Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P615T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC3A1 NM_000341.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.07
• Publications: 0 publications found

Genes affected

SLC3A1 (HGNC:11025): (solute carrier family 3 member 1) This gene encodes a type II membrane glycoprotein which is one of the components of the renal amino acid transporter which transports neutral and basic amino acids in the renal tubule and intestinal tract. Mutations and deletions in this gene are associated with cystinuria. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

PREPL (HGNC:30228): (prolyl endopeptidase like) The protein encoded by this gene belongs to the prolyl oligopeptidase subfamily of serine peptidases. Mutations in this gene have been associated with hypotonia-cystinuria syndrome, also known as the 2p21 deletion syndrome. Several alternatively spliced transcript variants encoding either the same or different isoforms have been described for this gene.[provided by RefSeq, Jan 2010]

PREPL Gene-Disease associations (from GenCC):

• hypotonia-cystinuria syndrome

  Inheritance: AR Classification: STRONG Submitted by: G2P
• myasthenic syndrome, congenital, 22

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

ENSG00000285542 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: -3.1434 (below the threshold of 3.09). Trascript score misZ: -3.2509 (below the threshold of 3.09). GenCC associations: The gene is linked to cystinuria type A, cystinuria.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000341.4. 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
	SLC3A1	NM_000341.4	MANE Select	c.1843_1845delCCCinsTCT	p.Pro615Ser	missense	N/A	NP_000332.2	Q07837-1
	PREPL	NM_001171613.2	MANE Select	c.*930_*932delGGGinsAGA		3_prime_UTR	Exon 14 of 14	NP_001165084.1	Q4J6C6-4
	PREPL	NM_001171603.1		c.*930_*932delGGGinsAGA		3_prime_UTR	Exon 15 of 15	NP_001165074.1	Q4J6C6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC3A1	ENST00000260649.11	TSL:1 MANE Select	c.1843_1845delCCCinsTCT	p.Pro615Ser	missense	N/A	ENSP00000260649.6	Q07837-1
	SLC3A1	ENST00000409380.5	TSL:1	c.1009_1011delCCCinsTCT	p.Pro337Ser	missense	N/A	ENSP00000386709.1	Q07837-2
	SLC3A1	ENST00000409740.3	TSL:1	c.736_738delCCCinsTCT	p.Pro246Ser	missense	N/A	ENSP00000386677.3	Q07837-4

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-44547563;