chr6-154406439-G-A

Position:

• chr6-154406439-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173515.4(CNKSR3):​c.1583C>T​(p.Ser528Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign 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: 6.00

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1885919).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNKSR3	NM_173515.4	c.1583C>T	p.Ser528Phe	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.1583C>T	p.Ser528Phe	missense_variant	13/13	1	NM_173515.4	ENSP00000475915.1
CNKSR3	ENST00000479339.5	c.1343C>T	p.Ser448Phe	missense_variant	13/13	1		ENSP00000418975.1
ENSG00000288520	ENST00000673182.1	c.1369+3904C>T		intron_variant				ENSP00000499846.1
CNKSR3	ENST00000433165.6	n.1371C>T		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

Feb 10, 2023

The c.1583C>T (p.S528F) alteration is located in exon 13 (coding exon 13) of the CNKSR3 gene. This alteration results from a C to T substitution at nucleotide position 1583, causing the serine (S) at amino acid position 528 to be replaced by a phenylalanine (F). 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	Benign	0.099
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L;.
PROVEAN	Benign	-1.9	.;N
REVEL	Benign	0.15
Sift	Uncertain	0.029	.;D
Sift4G	Benign	0.094	T;T
Polyphen		0.23	B;.
Vest4		0.096
MutPred		0.46		Loss of phosphorylation at S528 (P = 0.0167);.;
MVP		0.50
MPC		0.42
ClinPred		0.76	D
GERP RS		4.9
Varity_R		0.090
gMVP		0.28

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: chr6-154727573; COSMIC: COSV101401392; COSMIC: COSV101401392;