12-99649333-A-C

Position:

• chr12-99649333-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_153364.4(GARIN6):​c.661A>C​(p.Ser221Arg) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GARIN6 NM_153364.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.589

Genes affected

GARIN6 (HGNC:28594): (golgi associated RAB2 interactor family member 6)

ANKS1B (HGNC:24600): (ankyrin repeat and sterile alpha motif domain containing 1B) This gene encodes a multi-domain protein that is predominantly expressed in brain and testis. This protein interacts with amyloid beta protein precursor (AbetaPP) and may have a role in normal brain development, and in the pathogenesis of Alzheimer's disease. Expression of this gene has been shown to be elevated in patients with pre-B cell acute lymphocytic leukemia associated with t(1;19) translocation. Alternatively spliced transcript variants encoding different isoforms (some with different subcellular localization, PMID:15004329) have been described for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04052958).
• BP6: Variant 12-99649333-A-C is Benign according to our data. Variant chr12-99649333-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2495078.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GARIN6	NM_153364.4	c.661A>C	p.Ser221Arg	missense_variant	2/2	ENST00000324341.2
ANKS1B	NM_001352186.2	c.1272+5734T>G		intron_variant		ENST00000683438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GARIN6	ENST00000324341.2	c.661A>C	p.Ser221Arg	missense_variant	2/2	1	NM_153364.4	P1
ANKS1B	ENST00000683438.2	c.1272+5734T>G		intron_variant			NM_001352186.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.21
DANN	Benign	0.74
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.20	N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.021
Sift	Benign	1.0	T
Sift4G	Benign	0.87	T
Polyphen		0.0010	B
Vest4		0.049
MutPred		0.34		Gain of catalytic residue at R222 (P = 0.0013);
MVP		0.085
MPC		0.072
ClinPred		0.060	T
GERP RS		1.6
Varity_R		0.024
gMVP		0.023

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: chr12-100043111;