rs2817191

Variant names:

• chr6-24564312-A-G
• rs2817191
• NM_014809.4:c.2321T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014809.4(KIAA0319):​c.2321T>C​(p.Val774Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,613,504 control chromosomes in the GnomAD database, including 1,212 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.050 (419 hom., cov: 32)
  • Exomes 𝑓: 0.023 (793 hom.)
• Consequence: KIAA0319 NM_014809.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.20

Genes affected

KIAA0319 (HGNC:21580): (KIAA0319) This gene encodes a transmembrane protein that contains a large extracellular domain with multiple polycystic kidney disease (PKD) domains. The encoded protein may play a role in the development of the cerebral cortex by regulating neuronal migration and cell adhesion. Single nucleotide polymorphisms in this gene are associated with dyslexia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015754402).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIAA0319	NM_014809.4	c.2321T>C	p.Val774Ala	missense_variant	Exon 15 of 21	ENST00000378214.8	NP_055624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIAA0319	ENST00000378214.8	c.2321T>C	p.Val774Ala	missense_variant	Exon 15 of 21	1	NM_014809.4	ENSP00000367459.3

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7564 AN: 152116 Hom.: 417 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0417

GnomAD3 exomes AF: 0.0209 AC: 5232 AN: 250738 Hom.: 198 AF XY: 0.0180 AC XY: 2443 AN XY: 135552

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.000870

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.0200

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.0235 AC: 34299 AN: 1461270 Hom.: 793 Cov.: 31 AF XY: 0.0223 AC XY: 16240 AN XY: 726964

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.00343

Gnomad4 NFE exome AF: 0.0241

Gnomad4 OTH exome AF: 0.0257

GnomAD4 genome AF: 0.0497 AC: 7571 AN: 152234 Hom.: 419 Cov.: 32 AF XY: 0.0467 AC XY: 3479 AN XY: 74436

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.0224

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.0207

Gnomad4 OTH AF: 0.0413

Alfa AF: 0.0231 Hom.: 178

Bravo AF: 0.0561

TwinsUK AF: 0.0243 AC: 90

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.133 AC: 587

ESP6500EA AF: 0.0198 AC: 170

ExAC AF: 0.0230 AC: 2794

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0189

EpiControl AF: 0.0196

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.1
DANN	Benign	0.39
DEOGEN2	Benign	0.00035	.;.;.;.;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0094	N
LIST_S2	Benign	0.055	T;T;T;T;.;T
MetaRNN	Benign	0.0016	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.7	.;.;N;.;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.5	.;N;N;N;N;N
REVEL	Benign	0.059
Sift	Benign	1.0	.;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	.;.;.;B;B;B
Vest4		0.028
MPC		0.13
ClinPred		0.0024	T
GERP RS		0.76
Varity_R		0.033
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs2817191; hg19: chr6-24564540;