rs1288917959

Variant names:

• chr6-154410382-C-T
• rs1288917959
• NM_173515.4:c.1330G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173515.4(CNKSR3):​c.1330G>A​(p.Val444Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CNKSR3 NM_173515.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28279927).

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.1330G>A	p.Val444Met	missense	Exon 12 of 13	NP_775786.2	Q6P9H4-1
	CNKSR3	NM_001368116.1		c.1348G>A	p.Val450Met	missense	Exon 12 of 13	NP_001355045.1
	CNKSR3	NM_001368117.1		c.1330G>A	p.Val444Met	missense	Exon 12 of 13	NP_001355046.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNKSR3	ENST00000607772.6	TSL:1 MANE Select	c.1330G>A	p.Val444Met	missense	Exon 12 of 13	ENSP00000475915.1	Q6P9H4-1
	ENSG00000288520	ENST00000673182.1		c.1330G>A	p.Val444Met	missense	Exon 12 of 22	ENSP00000499846.1
	CNKSR3	ENST00000479339.5	TSL:1	c.1090G>A	p.Val364Met	missense	Exon 12 of 13	ENSP00000418975.1	A0A5H1ZRR2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251418 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461866 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

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: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.083
Sift	Benign	0.10	T
Sift4G	Benign	0.11	T
Polyphen		0.66	P
Vest4		0.32
MutPred		0.55		Gain of disorder (P = 0.012)
MVP		0.47
MPC		0.72
ClinPred		0.71	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.092
gMVP		0.25
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1288917959; hg19: chr6-154731516;