14-104948892-T-G

Variant names:

• chr14-104948892-T-G
• rs10134675
• NM_138420.4:c.6559A>C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_138420.4(AHNAK2):​c.6559A>C​(p.Met2187Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,590,774 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00013 (2 hom.)
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.85

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052985847).
• BP6: Variant 14-104948892-T-G is Benign according to our data. Variant chr14-104948892-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2672573.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHNAK2	NM_138420.4	c.6559A>C	p.Met2187Leu	missense_variant	Exon 7 of 7	ENST00000333244.6	NP_612429.2
AHNAK2	NM_001350929.2	c.6259A>C	p.Met2087Leu	missense_variant	Exon 7 of 7		NP_001337858.1
AHNAK2	XM_024449463.2	c.6259A>C	p.Met2087Leu	missense_variant	Exon 7 of 7		XP_024305231.1
AHNAK2	XM_047430904.1	c.6259A>C	p.Met2087Leu	missense_variant	Exon 7 of 7		XP_047286860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHNAK2	ENST00000333244.6	c.6559A>C	p.Met2187Leu	missense_variant	Exon 7 of 7	5	NM_138420.4	ENSP00000353114.4
AHNAK2	ENST00000557457.1	c.-221+4989A>C		intron_variant	Intron 1 of 2	1		ENSP00000450998.1
AHNAK2	ENST00000555122.1	n.6687A>C		non_coding_transcript_exon_variant	Exon 6 of 6	5

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 27 AN: 137330 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000579

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000228

Gnomad SAS AF: 0.00149

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000956

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000284 AC: 61 AN: 214968 Hom.: 0 AF XY: 0.000345 AC XY: 40 AN XY: 115920

Gnomad AFR exome AF: 0.000148

Gnomad AMR exome AF: 0.000726

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000611

Gnomad SAS exome AF: 0.000564

Gnomad FIN exome AF: 0.0000532

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.000564

GnomAD4 exome AF: 0.000129 AC: 187 AN: 1453340 Hom.: 2 Cov.: 114 AF XY: 0.000148 AC XY: 107 AN XY: 723012

Gnomad4 AFR exome AF: 0.000183

Gnomad4 AMR exome AF: 0.000837

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.000317

Gnomad4 SAS exome AF: 0.000480

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000730

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome AF: 0.000196 AC: 27 AN: 137434 Hom.: 0 Cov.: 24 AF XY: 0.000195 AC XY: 13 AN XY: 66582

Gnomad4 AFR AF: 0.000164

Gnomad4 AMR AF: 0.000578

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000229

Gnomad4 SAS AF: 0.00149

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000956

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000575 Hom.: 1683

ExAC AF: 0.000331 AC: 40

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AHNAK2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.11
DANN	Benign	0.35
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.060	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.012
Sift	Benign	0.34	T
Sift4G	Benign	0.30	T
Polyphen		0.074	B
Vest4		0.064
MutPred		0.27		Gain of catalytic residue at P2190 (P = 0.0261);
MVP		0.014
ClinPred		0.0018	T
GERP RS		-0.58
Varity_R		0.030
gMVP		0.0041

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: rs10134675; hg19: chr14-105415229;