chr2-237510678-A-G

Position:

• chr2-237510678-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024101.7(MLPH):​c.215A>G​(p.Gln72Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 1,613,788 control chromosomes in the GnomAD database, including 285 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (264 hom.)
• Consequence: MLPH NM_024101.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.06

Genes affected

MLPH (HGNC:29643): (melanophilin) This gene encodes a member of the exophilin subfamily of Rab effector proteins. The protein forms a ternary complex with the small Ras-related GTPase Rab27A in its GTP-bound form and the motor protein myosin Va. A similar protein complex in mouse functions to tether pigment-producing organelles called melanosomes to the actin cytoskeleton in melanocytes, and is required for visible pigmentation in the hair and skin. A mutation in this gene results in Griscelli syndrome type 3, which is characterized by a silver-gray hair color and abnormal pigment distribution in the hair shaft. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00254789).
• BP6: Variant 2-237510678-A-G is Benign according to our data. Variant chr2-237510678-A-G is described in ClinVar as [Benign]. Clinvar id is 1599849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLPH	NM_024101.7	c.215A>G	p.Gln72Arg	missense_variant	3/16	ENST00000264605.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLPH	ENST00000264605.8	c.215A>G	p.Gln72Arg	missense_variant	3/16	1	NM_024101.7	A2

Frequencies

GnomAD3 genomes AF: 0.00868 AC: 1321 AN: 152226 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00888

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0239

Gnomad SAS AF: 0.0499

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0167 AC: 4201 AN: 251198 Hom.: 96 AF XY: 0.0177 AC XY: 2401 AN XY: 135876

Gnomad AFR exome AF: 0.00918

Gnomad AMR exome AF: 0.0307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0266

Gnomad SAS exome AF: 0.0566

Gnomad FIN exome AF: 0.0235

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.00680 AC: 9932 AN: 1461444 Hom.: 264 Cov.: 31 AF XY: 0.00802 AC XY: 5827 AN XY: 727004

Gnomad4 AFR exome AF: 0.00830

Gnomad4 AMR exome AF: 0.0295

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0322

Gnomad4 SAS exome AF: 0.0538

Gnomad4 FIN exome AF: 0.0235

Gnomad4 NFE exome AF: 0.000540

Gnomad4 OTH exome AF: 0.00914

GnomAD4 genome AF: 0.00868 AC: 1323 AN: 152344 Hom.: 21 Cov.: 33 AF XY: 0.0108 AC XY: 808 AN XY: 74494

Gnomad4 AFR AF: 0.00887

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0240

Gnomad4 SAS AF: 0.0501

Gnomad4 FIN AF: 0.0256

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00223 Hom.: 5

Bravo AF: 0.00788

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0161 AC: 1959

Asia WGS AF: 0.0440 AC: 154 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.9
DANN	Benign	0.33
DEOGEN2	Benign	0.16	T;.;T;.;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.19	T;T;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	.;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.8	N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.81	T;T;T;T;T
Sift4G	Benign	0.71	T;T;T;T;T
Polyphen		0.0	.;.;B;B;.
Vest4		0.062, 0.064, 0.081, 0.080
MPC		0.11
ClinPred		0.0012	T
GERP RS		1.1
Varity_R		0.050
gMVP		0.41

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: rs80292002; hg19: chr2-238419321;