6-154406574-C-T

Variant names:

• chr6-154406574-C-T
• rs925966534
• NM_173515.4:c.1448G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_173515.4(CNKSR3):​c.1448G>A​(p.Arg483Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R483W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CNKSR3 NM_173515.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173515.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNKSR3	NM_173515.4	MANE Select	c.1448G>A	p.Arg483Gln	missense	Exon 13 of 13	NP_775786.2	Q6P9H4-1
	CNKSR3	NM_001368116.1		c.1466G>A	p.Arg489Gln	missense	Exon 13 of 13	NP_001355045.1
	CNKSR3	NM_001368118.1		c.1208G>A	p.Arg403Gln	missense	Exon 13 of 13	NP_001355047.1	A0A5H1ZRR2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNKSR3	ENST00000607772.6	TSL:1 MANE Select	c.1448G>A	p.Arg483Gln	missense	Exon 13 of 13	ENSP00000475915.1	Q6P9H4-1
	CNKSR3	ENST00000479339.5	TSL:1	c.1208G>A	p.Arg403Gln	missense	Exon 13 of 13	ENSP00000418975.1	A0A5H1ZRR2
	ENSG00000288520	ENST00000673182.1		c.1369+3769G>A		intron	N/A	ENSP00000499846.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.039
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.7
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.069
Sift	Benign	0.12	T
Sift4G	Benign	0.27	T
Polyphen		0.017	B
Vest4		0.077
MutPred		0.58		Loss of catalytic residue at R483 (P = 0.0069)
MVP		0.51
MPC		0.30
ClinPred		0.83	D
GERP RS		4.9
Varity_R		0.056
gMVP		0.24
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs925966534; hg19: chr6-154727708; COSMIC: COSV70481099; COSMIC: COSV70481099;