chr5-126469709-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_023927.4(GRAMD2B):​c.236C>A​(p.Ala79Glu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A79V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GRAMD2B NM_023927.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.261
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059455782).

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>A	p.Ala79Glu	missense	Exon 3 of 14	NP_076416.2	Q96HH9-1
	GRAMD2B	NM_001146319.3		c.281C>A	p.Ala94Glu	missense	Exon 3 of 14	NP_001139791.1	Q96HH9-3
	GRAMD2B	NM_001349544.2		c.260C>A	p.Ala87Glu	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>A	p.Ala79Glu	missense	Exon 3 of 14	ENSP00000285689.3	Q96HH9-1
	GRAMD2B	ENST00000921003.1		c.236C>A	p.Ala79Glu	missense	Exon 3 of 15	ENSP00000591062.1
	GRAMD2B	ENST00000513040.5	TSL:2	c.281C>A	p.Ala94Glu	missense	Exon 3 of 14	ENSP00000426120.1	Q96HH9-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000245 AC: 34 AN: 1387604 Hom.: 0 Cov.: 30 AF XY: 0.0000173 AC XY: 12 AN XY: 692204

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000631 AC: 2 AN: 31710

American (AMR) AF: 0.00 AC: 0 AN: 43730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24592

East Asian (EAS) AF: 0.00 AC: 0 AN: 37312

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

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49594

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

European-Non Finnish (NFE) AF: 0.0000275 AC: 29 AN: 1053126

Other (OTH) AF: 0.0000352 AC: 2 AN: 56866

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.87
DEOGEN2	Benign	0.0097	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.26
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.14
Sift	Benign	0.095	T
Sift4G	Benign	0.33	T
Polyphen		0.11	B
Vest4		0.19
MutPred		0.20		Gain of loop (P = 0.069)
MVP		0.27
MPC		0.30
ClinPred		0.033	T
GERP RS		-2.3
Varity_R		0.067
gMVP		0.35
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs1032274833; hg19: chr5-125805401;