19-15400817-C-A

Variant names:

• chr19-15400817-C-A
• NM_014371.4:c.961G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014371.4(AKAP8L):​c.961G>T​(p.Ala321Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AKAP8L NM_014371.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0390
• Publications: 0 publications found

Genes affected

AKAP8L (HGNC:29857): (A-kinase anchoring protein 8 like) Enables histone deacetylase binding activity and lamin binding activity. Involved in several processes, including mitotic chromosome condensation; regulation of histone modification; and regulation of mRNA export from nucleus. Located in chromatin; cytoplasm; and nuclear lumen. Part of ribonucleoprotein complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053677052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP8L	NM_014371.4	c.961G>T	p.Ala321Ser	missense_variant	Exon 7 of 14	ENST00000397410.10	NP_055186.3
AKAP8L	NM_001291478.2	c.778G>T	p.Ala260Ser	missense_variant	Exon 7 of 14		NP_001278407.1
AKAP8L	NR_111971.2	n.924G>T		non_coding_transcript_exon_variant	Exon 8 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP8L	ENST00000397410.10	c.961G>T	p.Ala321Ser	missense_variant	Exon 7 of 14	1	NM_014371.4	ENSP00000380557.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.961G>T (p.A321S) alteration is located in exon 7 (coding exon 7) of the AKAP8L gene. This alteration results from a G to T substitution at nucleotide position 961, causing the alanine (A) at amino acid position 321 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.2
DANN	Benign	0.83
DEOGEN2	Benign	0.029	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.
PhyloP100		-0.039
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.76	N;.
REVEL	Benign	0.040
Sift	Benign	0.11	T;.
Sift4G	Benign	0.37	T;T
Polyphen		0.0050	B;.
Vest4		0.095
MutPred		0.15		Gain of phosphorylation at A321 (P = 0.0031);.;
MVP		0.51
MPC		0.45
ClinPred		0.047	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.017
Mutation Taster		=96/4	polymorphism

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

hg19: chr19-15511628;