chr12-6906609-T-C

Position:

• chr12-6906609-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001135217.2(LRRC23):​c.437T>C​(p.Ile146Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRRC23 NM_001135217.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.84

Genes affected

LRRC23 (HGNC:19138): (leucine rich repeat containing 23) Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

LRRC23 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC23	NM_001135217.2	c.437T>C	p.Ile146Thr	missense_variant	4/8	ENST00000443597.7	NP_001128689.1
LRRC23	NM_201650.3	c.437T>C	p.Ile146Thr	missense_variant	4/8		NP_964013.1
LRRC23	NM_006992.4	c.437T>C	p.Ile146Thr	missense_variant	4/7		NP_008923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC23	ENST00000443597.7	c.437T>C	p.Ile146Thr	missense_variant	4/8	1	NM_001135217.2	ENSP00000390932.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2024

The c.437T>C (p.I146T) alteration is located in exon 4 (coding exon 3) of the LRRC23 gene. This alteration results from a T to C substitution at nucleotide position 437, causing the isoleucine (I) at amino acid position 146 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;.;.;T;T;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;D;D;D;D;.
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.6	.;H;.;H;H;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.2	D;D;.;D;D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0030	D;D;.;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D
Vest4		0.93
MutPred		0.78		Gain of catalytic residue at A142 (P = 0.0028);Gain of catalytic residue at A142 (P = 0.0028);Gain of catalytic residue at A142 (P = 0.0028);Gain of catalytic residue at A142 (P = 0.0028);Gain of catalytic residue at A142 (P = 0.0028);Gain of catalytic residue at A142 (P = 0.0028);Gain of catalytic residue at A142 (P = 0.0028);
MVP		0.79
MPC		0.69
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.43
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs1944956317; hg19: chr12-7015773;