NM_001286611.2:c.2199A>C

Variant names:

• chr6-138908685-T-G
• NM_001286611.2:c.2199A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_001286611.2(REPS1):​c.2199A>C​(p.Ser733Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: REPS1 NM_001286611.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.313
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.053).
• BP6: Variant 6-138908685-T-G is Benign according to our data. Variant chr6-138908685-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2123259.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.313 with no splicing effect.

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.2199A>C	p.Ser733Ser	synonymous	Exon 18 of 20	NP_001273540.1	Q96D71-1
	REPS1	NM_031922.5		c.2196A>C	p.Ser732Ser	synonymous	Exon 18 of 20	NP_114128.3
	REPS1	NM_001128617.3		c.2118A>C	p.Ser706Ser	synonymous	Exon 17 of 19	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.2199A>C	p.Ser733Ser	synonymous	Exon 18 of 20	ENSP00000392065.2	Q96D71-1
	REPS1	ENST00000258062.9	TSL:1	c.2196A>C	p.Ser732Ser	synonymous	Exon 18 of 20	ENSP00000258062.5	Q96D71-3
	REPS1	ENST00000409812.6	TSL:1	c.1926A>C	p.Ser642Ser	synonymous	Exon 15 of 17	ENSP00000386699.2	Q96D71-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely 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
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.6
DANN	Benign	0.79
PhyloP100		0.31
PromoterAI		-0.022	Neutral

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

hg19: chr6-139229822;