chr14-104938542-G-C

Position:

• chr14-104938542-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138420.4(AHNAK2):​c.16909C>G​(p.Pro5637Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,052 control chromosomes in the GnomAD database, with no homozygous occurrence. 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.90

Genes affected

AHNAK2 (HGNC:20125): (AHNAK nucleoprotein 2) This gene encodes a large nucleoprotein. The encoded protein has a tripartite domain structure with a relatively short N-terminus and a long C-terminus, separated by a large body of repeats. The N-terminal PSD-95/Discs-large/ZO-1 (PDZ)-like domain is thought to function in the formation of stable homodimers. The encoded protein may play a role in calcium signaling by associating with calcium channel proteins. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2017]

AHNAK2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037878394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHNAK2	NM_138420.4	c.16909C>G	p.Pro5637Ala	missense_variant	7/7	ENST00000333244.6	NP_612429.2
AHNAK2	NM_001350929.2	c.16609C>G	p.Pro5537Ala	missense_variant	7/7		NP_001337858.1
AHNAK2	XM_024449463.2	c.16609C>G	p.Pro5537Ala	missense_variant	7/7		XP_024305231.1
AHNAK2	XM_047430904.1	c.16609C>G	p.Pro5537Ala	missense_variant	7/7		XP_047286860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHNAK2	ENST00000333244.6	c.16909C>G	p.Pro5637Ala	missense_variant	7/7	5	NM_138420.4	ENSP00000353114.4
AHNAK2	ENST00000557457.1	c.1903C>G	p.Pro635Ala	missense_variant	3/3	1		ENSP00000450998.1
AHNAK2	ENST00000555122.1	n.17037C>G		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461052 Hom.: 0 Cov.: 73 AF XY: 0.00 AC XY: 0 AN XY: 726764

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Oct 03, 2024

The c.16909C>G (p.P5637A) alteration is located in exon 7 (coding exon 7) of the AHNAK2 gene. This alteration results from a C to G substitution at nucleotide position 16909, causing the proline (P) at amino acid position 5637 to be replaced by an alanine (A). 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	0.064
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.043
DANN	Benign	0.47
DEOGEN2	Benign	0.022	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.038	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.83	.;L
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-4.0	D;N
REVEL	Benign	0.0070
Sift	Benign	0.47	T;T
Sift4G	Benign	0.83	T;T
Polyphen		0.0050	.;B
Vest4		0.075
MutPred		0.32		.;Loss of loop (P = 0.0075);
MVP		0.014
ClinPred		0.049	T
GERP RS		-3.6
Varity_R		0.018
gMVP		0.0083

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-105404879;