rs11231128

chr11-62523247-A-G

Variant summary

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

The NM_001620.3(AHNAK):c.11170T>C(p.Ser3724Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0311 in 1,609,238 control chromosomes in the GnomAD database, including 1,096 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.049 (319 hom., cov: 32)
  • Exomes 𝑓: 0.029 (777 hom.)
• Consequence: AHNAK NM_001620.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.90

Genes affected

AHNAK (HGNC:347): (AHNAK nucleoprotein) The protein encoded by this gene is a large (700 kDa) structural scaffold protein consisting of a central domain with 128 aa repeats. The encoded protein may play a role in such diverse processes as blood-brain barrier formation, cell structure and migration, cardiac calcium channel regulation, and tumor metastasis. A much shorter variant encoding a 17 kDa isoform exists for this gene, and the shorter isoform initiates a feedback loop that regulates alternative splicing of this gene. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014526248).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHNAK	NM_001620.3	c.11170T>C	p.Ser3724Pro	missense_variant	5/5	ENST00000378024.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHNAK	ENST00000378024.9	c.11170T>C	p.Ser3724Pro	missense_variant	5/5	2	NM_001620.3
AHNAK	ENST00000257247.11	c.342+11756T>C		intron_variant		1		P1
AHNAK	ENST00000530124.5	c.342+11756T>C		intron_variant		3
AHNAK	ENST00000533365.5	c.342+11756T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0490 AC: 7209 AN: 147254 Hom.: 314 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0457

Gnomad EAS AF: 0.00976

Gnomad SAS AF: 0.0293

Gnomad FIN AF: 0.00976

Gnomad MID AF: 0.0719

Gnomad NFE AF: 0.0273

Gnomad OTH AF: 0.0460

GnomAD3 exomes AF: 0.0307 AC: 7703 AN: 251274 Hom.: 196 AF XY: 0.0301 AC XY: 4086 AN XY: 135790

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0163

Gnomad ASJ exome AF: 0.0395

Gnomad EAS exome AF: 0.0119

Gnomad SAS exome AF: 0.0286

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.0309

Gnomad OTH exome AF: 0.0339

GnomAD4 exome AF: 0.0293 AC: 42870 AN: 1461866 Hom.: 777 Cov.: 83 AF XY: 0.0295 AC XY: 21457 AN XY: 727240

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.0178

Gnomad4 ASJ exome AF: 0.0394

Gnomad4 EAS exome AF: 0.00874

Gnomad4 SAS exome AF: 0.0286

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.0283

Gnomad4 OTH exome AF: 0.0360

GnomAD4 genome AF: 0.0492 AC: 7253 AN: 147372 Hom.: 319 Cov.: 32 AF XY: 0.0488 AC XY: 3512 AN XY: 71896

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.0346

Gnomad4 ASJ AF: 0.0457

Gnomad4 EAS AF: 0.00958

Gnomad4 SAS AF: 0.0292

Gnomad4 FIN AF: 0.00976

Gnomad4 NFE AF: 0.0273

Gnomad4 OTH AF: 0.0504

Alfa AF: 0.0328 Hom.: 293

Bravo AF: 0.0517

TwinsUK AF: 0.0275 AC: 102

ALSPAC AF: 0.0283 AC: 109

ESP6500AA AF: 0.0972 AC: 428

ESP6500EA AF: 0.0258 AC: 222

ExAC AF: 0.0345 AC: 4195

Asia WGS AF: 0.0370 AC: 127 AN: 3478

EpiCase AF: 0.0305

EpiControl AF: 0.0321

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	13
Dann	Benign	0.22
DEOGEN2	Benign	0.076	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.0	N
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.028
ClinPred		0.0058	T
GERP RS		4.4
Varity_R		0.056
gMVP		0.019

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: rs11231128; hg19: chr11-62290719;