14-24097080-C-T

Position:

• chr14-24097080-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000216780.9(PCK2):​c.218C>T​(p.Thr73Ile) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: PCK2 ENST00000216780.9 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0850

Genes affected

PCK2 (HGNC:8725): (phosphoenolpyruvate carboxykinase 2, mitochondrial) This gene encodes a mitochondrial enzyme that catalyzes the conversion of oxaloacetate to phosphoenolpyruvate in the presence of guanosine triphosphate (GTP). A cytosolic form of this protein is encoded by a different gene and is the key enzyme of gluconeogenesis in the liver. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2014]

NRL (HGNC:8002): (neural retina leucine zipper) This gene encodes a basic motif-leucine zipper transcription factor of the Maf subfamily. The encoded protein is conserved among vertebrates and is a critical intrinsic regulator of photoceptor development and function. Mutations in this gene have been associated with retinitis pigmentosa and retinal degenerative diseases. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036484897).
• BP6: Variant 14-24097080-C-T is Benign according to our data. Variant chr14-24097080-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2248937.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCK2	NM_004563.4	c.218C>T	p.Thr73Ile	missense_variant	2/10	ENST00000216780.9	NP_004554.3
NRL	NM_001354768.3	c.-27-14205G>A		intron_variant		ENST00000561028.6	NP_001341697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCK2	ENST00000216780.9	c.218C>T	p.Thr73Ile	missense_variant	2/10	1	NM_004563.4	ENSP00000216780	P1
NRL	ENST00000561028.6	c.-27-14205G>A		intron_variant		2	NM_001354768.3	ENSP00000454062	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.35
DANN	Benign	0.89
DEOGEN2	Benign	0.0014	T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.053	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.036	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-1.3	.;N;N
MutationTaster	Benign	1.0	D;D;D;D;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.6	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.20
MutPred		0.54		.;Loss of disorder (P = 0.0514);Loss of disorder (P = 0.0514);
MVP		0.28
MPC		0.061
ClinPred		0.26	T
GERP RS		-6.0
Varity_R		0.070
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-24566289; COSMIC: COSV99394358; COSMIC: COSV99394358;