5-126469709-C-T

Variant names:

• chr5-126469709-C-T
• rs1032274833
• NM_023927.4:c.236C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_023927.4(GRAMD2B):​c.236C>T​(p.Ala79Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000325 in 1,539,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict 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. A79T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: GRAMD2B NM_023927.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.261
• Publications: 1 publications found

Genes affected

GRAMD2B (HGNC:24911): (GRAM domain containing 2B) Enables identical protein binding activity. Located in cytoplasmic microtubule. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000250602 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023927.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRAMD2B	NM_023927.4	MANE Select	c.236C>T	p.Ala79Val	missense	Exon 3 of 14	NP_076416.2	Q96HH9-1
	GRAMD2B	NM_001146319.3		c.281C>T	p.Ala94Val	missense	Exon 3 of 14	NP_001139791.1	Q96HH9-3
	GRAMD2B	NM_001349544.2		c.260C>T	p.Ala87Val	missense	Exon 4 of 15	NP_001336473.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRAMD2B	ENST00000285689.8	TSL:1 MANE Select	c.236C>T	p.Ala79Val	missense	Exon 3 of 14	ENSP00000285689.3	Q96HH9-1
	GRAMD2B	ENST00000921003.1		c.236C>T	p.Ala79Val	missense	Exon 3 of 15	ENSP00000591062.1
	GRAMD2B	ENST00000513040.5	TSL:2	c.281C>T	p.Ala94Val	missense	Exon 3 of 14	ENSP00000426120.1	Q96HH9-3

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151254 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000288 AC: 4 AN: 1387880 Hom.: 0 Cov.: 30 AF XY: 0.00000144 AC XY: 1 AN XY: 692324

African (AFR) AF: 0.00 AC: 0 AN: 31722

American (AMR) AF: 0.00 AC: 0 AN: 43734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24598

East Asian (EAS) AF: 0.00 AC: 0 AN: 37318

South Asian (SAS) AF: 0.00 AC: 0 AN: 85144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.00000380 AC: 4 AN: 1053356

Other (OTH) AF: 0.00 AC: 0 AN: 56874

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151254 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73886

African (AFR) AF: 0.00 AC: 0 AN: 41232

American (AMR) AF: 0.00 AC: 0 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5052

South Asian (SAS) AF: 0.00 AC: 0 AN: 4620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67832

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.84
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.26
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.12
Sift	Benign	0.21	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.023
MutPred		0.23		Gain of sheet (P = 0.1945)
MVP		0.24
MPC		0.20
ClinPred		0.022	T
GERP RS		-2.3
Varity_R		0.033
gMVP		0.13
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: -32

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

Other links and lift over

dbSNP: rs1032274833; hg19: chr5-125805401;