2-237510643-C-A

Variant names:

• chr2-237510643-C-A
• NM_024101.7:c.180C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024101.7(MLPH):​c.180C>A​(p.Asn60Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N60N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MLPH NM_024101.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.84

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLPH	NM_024101.7	c.180C>A	p.Asn60Lys	missense_variant	Exon 3 of 16	ENST00000264605.8	NP_077006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLPH	ENST00000264605.8	c.180C>A	p.Asn60Lys	missense_variant	Exon 3 of 16	1	NM_024101.7	ENSP00000264605.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	4.0
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;.;D;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.77	T;T;T;T;T;T
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.4	.;.;L;L;L;L
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.1	D;D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Benign	0.067	T;T;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;D;D;.
Vest4		0.22, 0.24, 0.26
MutPred		0.46		Gain of ubiquitination at N60 (P = 0.0069);Gain of ubiquitination at N60 (P = 0.0069);Gain of ubiquitination at N60 (P = 0.0069);Gain of ubiquitination at N60 (P = 0.0069);Gain of ubiquitination at N60 (P = 0.0069);Gain of ubiquitination at N60 (P = 0.0069);
MVP		0.76
MPC		0.19
ClinPred		0.96	D
GERP RS		-0.88
Varity_R		0.54
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-238419286;