chr6-154410432-C-T

Variant names:

• chr6-154410432-C-T
• rs186911920
• NM_173515.4:c.1280G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_173515.4(CNKSR3):​c.1280G>A​(p.Gly427Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,611,552 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: CNKSR3 NM_173515.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.23
• 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.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.1280G>A	p.Gly427Asp	missense splice_region	Exon 12 of 13	NP_775786.2	Q6P9H4-1
	CNKSR3	NM_001368116.1		c.1298G>A	p.Gly433Asp	missense splice_region	Exon 12 of 13	NP_001355045.1
	CNKSR3	NM_001368117.1		c.1280G>A	p.Gly427Asp	missense splice_region	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.1280G>A	p.Gly427Asp	missense splice_region	Exon 12 of 13	ENSP00000475915.1	Q6P9H4-1
	ENSG00000288520	ENST00000673182.1		c.1280G>A	p.Gly427Asp	missense splice_region	Exon 12 of 22	ENSP00000499846.1
	CNKSR3	ENST00000479339.5	TSL:1	c.1040G>A	p.Gly347Asp	missense splice_region	Exon 12 of 13	ENSP00000418975.1	A0A5H1ZRR2

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

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: 0.000191

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.000263 AC: 66 AN: 251166 AF XY: 0.000332

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000297 AC: 433 AN: 1459254 Hom.: 0 Cov.: 29 AF XY: 0.000307 AC XY: 223 AN XY: 726148

African (AFR) AF: 0.0000599 AC: 2 AN: 33392

American (AMR) AF: 0.00105 AC: 47 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000320 AC: 355 AN: 1109742

Other (OTH) AF: 0.000464 AC: 28 AN: 60314

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74488

African (AFR) AF: 0.000168 AC: 7 AN: 41564

American (AMR) AF: 0.00229 AC: 35 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68036

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.000350 Hom.: 0

Bravo AF: 0.000824

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000164

EpiControl AF: 0.000296

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	Pathogenic	0.86
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.79
MPC		1.1
ClinPred		0.35	T
GERP RS		6.0
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		2.4
Varity_R		0.59
gMVP		0.59
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.020		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: rs186911920; hg19: chr6-154731566;