1-108830586-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152763.5(AKNAD1):c.1811G>C(p.Cys604Ser) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C604Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKNAD1 NM_152763.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

Genes affected

AKNAD1 (HGNC:28398): (AKNA domain containing 1) This gene encodes a protein which contains a domain found in an AT-hook-containing transcription factor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

LOC105378891 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.357713).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKNAD1	NM_152763.5	c.1811G>C	p.Cys604Ser	missense_variant	10/16	ENST00000370001.8
LOC105378891	XR_947687.3	n.123-3604C>G		intron_variant, non_coding_transcript_variant
AKNAD1	NR_049760.2	n.2023G>C		non_coding_transcript_exon_variant	9/14
LOC105378891	XR_007066273.1	n.148-3604C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKNAD1	ENST00000370001.8	c.1811G>C	p.Cys604Ser	missense_variant	10/16	1	NM_152763.5	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The c.1811G>C (p.C604S) alteration is located in exon 10 (coding exon 9) of the AKNAD1 gene. This alteration results from a G to C substitution at nucleotide position 1811, causing the cysteine (C) at amino acid position 604 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0042	T;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.0	L;.;L
MutationTaster	Benign	0.53	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.028	D;D;D
Sift4G	Benign	0.30	T;T;T
Polyphen		0.99	D;.;.
Vest4		0.41
MutPred		0.33		Gain of helix (P = 0.0034);.;Gain of helix (P = 0.0034);
MVP		0.25
MPC		0.17
ClinPred		0.80	D
GERP RS		4.0
Varity_R		0.21
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-109373208;