chr19-8322919-C-T

Variant names:

• chr19-8322919-C-T
• rs140801793
• NM_198471.3:c.2386G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_198471.3(KANK3):​c.2386G>A​(p.Glu796Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000532 in 1,511,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: KANK3 NM_198471.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12
• Publications: 4 publications found

Genes affected

KANK3 (HGNC:24796): (KN motif and ankyrin repeat domains 3) Predicted to be involved in negative regulation of actin filament polymerization. Predicted to be active in cytoplasm and cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

RPS28 (HGNC:10418): (ribosomal protein S28) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S28E family of ribosomal proteins. It is located in the cytoplasm. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

RPS28 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia 15 with mandibulofacial dysostosis

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016808003).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198471.3. 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
	KANK3	NM_198471.3	MANE Select	c.2386G>A	p.Glu796Lys	missense	Exon 11 of 11	NP_940873.2	Q6NY19-2
	RPS28	NM_001031.5	MANE Select	c.*664C>T		3_prime_UTR	Exon 4 of 4	NP_001022.1	P62857

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANK3	ENST00000330915.7	TSL:1 MANE Select	c.2386G>A	p.Glu796Lys	missense	Exon 11 of 11	ENSP00000328923.2	Q6NY19-2
	RPS28	ENST00000600659.3	TSL:1 MANE Select	c.*664C>T		3_prime_UTR	Exon 4 of 4	ENSP00000472469.1	P62857
	KANK3	ENST00000868864.1		c.2476G>A	p.Glu826Lys	missense	Exon 11 of 11	ENSP00000538923.1

Frequencies

GnomAD3 genomes AF: 0.000353 AC: 52 AN: 147136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000658

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000287 AC: 48 AN: 167326 AF XY: 0.000309

Gnomad AFR exome AF: 0.0000863

Gnomad AMR exome AF: 0.0000501

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000774

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000516

Gnomad OTH exome AF: 0.000278

GnomAD4 exome AF: 0.000551 AC: 752 AN: 1364418 Hom.: 0 Cov.: 28 AF XY: 0.000556 AC XY: 374 AN XY: 672094

African (AFR) AF: 0.00 AC: 0 AN: 28996

American (AMR) AF: 0.0000328 AC: 1 AN: 30510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21244

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35582

South Asian (SAS) AF: 0.0000938 AC: 7 AN: 74612

European-Finnish (FIN) AF: 0.0000197 AC: 1 AN: 50728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5366

European-Non Finnish (NFE) AF: 0.000684 AC: 726 AN: 1061630

Other (OTH) AF: 0.000287 AC: 16 AN: 55750

GnomAD4 genome AF: 0.000353 AC: 52 AN: 147242 Hom.: 0 Cov.: 32 AF XY: 0.000292 AC XY: 21 AN XY: 72004

African (AFR) AF: 0.000104 AC: 4 AN: 38458

American (AMR) AF: 0.000135 AC: 2 AN: 14816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3382

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.000658 AC: 44 AN: 66902

Other (OTH) AF: 0.00 AC: 0 AN: 2044

Alfa AF: 0.000549 Hom.: 0

Bravo AF: 0.000351

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000265 AC: 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	0.074
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.67
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.98	T
PhyloP100		1.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.0060
Sift	Benign	0.68	T
Sift4G	Benign	0.32	T
Polyphen		0.15	B
Vest4		0.18
MVP		0.12
ClinPred		0.0025	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
gMVP		0.25
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs140801793; hg19: chr19-8387803; COSMIC: COSV56846481; COSMIC: COSV56846481;