6-138907618-G-T

Variant names:

• chr6-138907618-G-T
• rs1299458394
• NM_001286611.2:c.2217-18C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001286611.2(REPS1):​c.2217-18C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000751 in 1,332,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: REPS1 NM_001286611.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.146
• Publications: 0 publications found

Genes affected

REPS1 (HGNC:15578): (RALBP1 associated Eps domain containing 1) This gene encodes a signaling adaptor protein with two EH domains that interacts with proteins that participate in signaling, endocytosis and cytoskeletal changes. The encoded protein has been found in association with intersectin 1 and Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 when intersectin 1 was isolated from clathrin-coated pits. The encoded protein has also been shown to interact with amphiphysin, a cytoplasmic protein at the surface of synaptic vesicles. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

REPS1 Gene-Disease associations (from GenCC):

• neurodegeneration with brain iron accumulation 7

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286611.2. 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
	REPS1	NM_001286611.2	MANE Select	c.2217-18C>A		intron	N/A	NP_001273540.1	Q96D71-1
	REPS1	NM_031922.5		c.2214-18C>A		intron	N/A	NP_114128.3
	REPS1	NM_001128617.3		c.2136-18C>A		intron	N/A	NP_001122089.1	Q96D71-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REPS1	ENST00000450536.7	TSL:1 MANE Select	c.2217-18C>A		intron	N/A	ENSP00000392065.2	Q96D71-1
	REPS1	ENST00000258062.9	TSL:1	c.2214-18C>A		intron	N/A	ENSP00000258062.5	Q96D71-3
	REPS1	ENST00000409812.6	TSL:1	c.1944-18C>A		intron	N/A	ENSP00000386699.2	Q96D71-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.51e-7 AC: 1 AN: 1332392 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 670202

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30640

American (AMR) AF: 0.00 AC: 0 AN: 43378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25138

East Asian (EAS) AF: 0.00 AC: 0 AN: 39082

South Asian (SAS) AF: 0.00 AC: 0 AN: 82502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5490

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 997642

Other (OTH) AF: 0.00 AC: 0 AN: 55908

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.6
DANN	Benign	0.60
PhyloP100		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1299458394; hg19: chr6-139228755;