rs2817191

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014809.4. 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
	KIAA0319	NM_014809.4	MANE Select	c.2321T>C	p.Val774Ala	missense	Exon 15 of 21	NP_055624.2	Q5VV43-1
	KIAA0319	NM_001168375.2		c.2321T>C	p.Val774Ala	missense	Exon 15 of 21	NP_001161847.1	Q5VV43-1
	KIAA0319	NM_001350403.2		c.2321T>C	p.Val774Ala	missense	Exon 15 of 21	NP_001337332.1	Q5VV43-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0319	ENST00000378214.8	TSL:1 MANE Select	c.2321T>C	p.Val774Ala	missense	Exon 15 of 21	ENSP00000367459.3	Q5VV43-1
	KIAA0319	ENST00000537886.5	TSL:1	c.2321T>C	p.Val774Ala	missense	Exon 15 of 19	ENSP00000439700.1	Q5VV43-4
	KIAA0319	ENST00000616673.4	TSL:1	c.554T>C	p.Val185Ala	missense	Exon 11 of 17	ENSP00000483665.1	A0A087X0U9

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

GnomAD2 exomes AF: 0.0209 AC: 5232 AN: 250738 AF XY: 0.0180

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 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

African (AFR) AF: 0.146 AC: 4888 AN: 33412

American (AMR) AF: 0.0132 AC: 591 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26134

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39700

South Asian (SAS) AF: 0.00189 AC: 163 AN: 86256

European-Finnish (FIN) AF: 0.00343 AC: 183 AN: 53420

Middle Eastern (MID) AF: 0.0201 AC: 116 AN: 5768

European-Non Finnish (NFE) AF: 0.0241 AC: 26740 AN: 1111486

Other (OTH) AF: 0.0257 AC: 1551 AN: 60370

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

African (AFR) AF: 0.137 AC: 5667 AN: 41502

American (AMR) AF: 0.0224 AC: 343 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4830

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0207 AC: 1408 AN: 68020

Other (OTH) AF: 0.0413 AC: 87 AN: 2106

Alfa AF: 0.0281 Hom.: 388

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 v4.9

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
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0094	N
LIST_S2	Benign	0.055	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.7	N
PhyloP100		3.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.059
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.13
ClinPred		0.0024	T
GERP RS		0.76
Varity_R		0.033
gMVP		0.21
Mutation Taster		=99/1	polymorphism (auto)

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: rs2817191; hg19: chr6-24564540; COSMIC: COSV107486748;