chr6-154406472-A-T

Position:

• chr6-154406472-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_173515.4(CNKSR3):​c.1550T>A​(p.Ile517Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNKSR3 NM_173515.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.82

Genes affected

CNKSR3 (HGNC:23034): (CNKSR family member 3) Predicted to be involved in negative regulation of ERK1 and ERK2 cascade; negative regulation of peptidyl-serine phosphorylation; and positive regulation of sodium ion transport. Predicted to act upstream of or within positive regulation of sodium ion transmembrane transporter activity. Predicted to be located in apical plasma membrane and cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000288520 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNKSR3	NM_173515.4	c.1550T>A	p.Ile517Asn	missense_variant	13/13	ENST00000607772.6	NP_775786.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNKSR3	ENST00000607772.6	c.1550T>A	p.Ile517Asn	missense_variant	13/13	1	NM_173515.4	ENSP00000475915.1
CNKSR3	ENST00000479339.5	c.1310T>A	p.Ile437Asn	missense_variant	13/13	1		ENSP00000418975.1
ENSG00000288520	ENST00000673182.1	c.1369+3871T>A		intron_variant				ENSP00000499846.1
CNKSR3	ENST00000433165.6	n.1338T>A		non_coding_transcript_exon_variant	10/10	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Aug 08, 2023

The c.1550T>A (p.I517N) alteration is located in exon 13 (coding exon 13) of the CNKSR3 gene. This alteration results from a T to A substitution at nucleotide position 1550, causing the isoleucine (I) at amino acid position 517 to be replaced by an asparagine (N). 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	0.74
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.4	M;.
PROVEAN	Benign	-1.6	.;N
REVEL	Benign	0.27
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.048	D;D
Polyphen		0.99	D;.
Vest4		0.86
MutPred		0.71		Loss of sheet (P = 0.0142);.;
MVP		0.65
MPC		1.2
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.68
gMVP		0.59

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: chr6-154727606;