chr6-79493636-G-C

Variant names:

• chr6-79493636-G-C
• rs121918165
• NM_001122769.3:c.835C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_181714.4(LCA5):​c.835C>G​(p.Gln279Glu) variant causes a missense 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q279Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LCA5 NM_181714.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58
• Publications: 0 publications found

Genes affected

LCA5 (HGNC:31923): (lebercilin LCA5) This gene encodes a protein that is thought to be involved in centrosomal or ciliary functions. Mutations in this gene cause Leber congenital amaurosis type V. Alternatively spliced transcript variants are described. [provided by RefSeq, Oct 2009]

LCA5 Gene-Disease associations (from GenCC):

• LCA5-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leber congenital amaurosis 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000231533 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a coiled_coil_region (size 194) in uniprot entity LCA5_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_181714.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3116548).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181714.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCA5	NM_001122769.3	MANE Select	c.835C>G	p.Gln279Glu	missense	Exon 4 of 8	NP_001116241.1
	LCA5	NM_181714.4		c.835C>G	p.Gln279Glu	missense	Exon 5 of 9	NP_859065.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCA5	ENST00000369846.9	TSL:1 MANE Select	c.835C>G	p.Gln279Glu	missense	Exon 4 of 8	ENSP00000358861.4
	LCA5	ENST00000392959.5	TSL:1	c.835C>G	p.Gln279Glu	missense	Exon 5 of 9	ENSP00000376686.1
	LCA5	ENST00000467898.3	TSL:5	c.835C>G	p.Gln279Glu	missense	Exon 4 of 7	ENSP00000474463.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.089	T
Eigen	Benign	0.062
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.23
Sift	Benign	0.16	T
Sift4G	Benign	0.48	T
Polyphen		0.86	P
Vest4		0.28
MutPred		0.13		Loss of MoRF binding (P = 0.03)
MVP		0.79
MPC		0.096
ClinPred		0.65	D
GERP RS		5.6
Varity_R		0.11
gMVP		0.054
Mutation Taster		=92/8	polymorphism

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: rs121918165; hg19: chr6-80203353;