2-237510643-C-T

Variant names:

• chr2-237510643-C-T
• rs2292878
• NM_024101.7:c.180C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024101.7(MLPH):​c.180C>T​(p.Asn60Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00672 in 1,613,750 control chromosomes in the GnomAD database, including 278 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (260 hom.)
• Consequence: MLPH NM_024101.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.84
• Publications: 1 publications found

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]

MLPH Gene-Disease associations (from GenCC):

• Griscelli syndrome type 3

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-237510643-C-T is Benign according to our data. Variant chr2-237510643-C-T is described in ClinVar as Benign. ClinVar VariationId is 1655837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.84 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0524 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024101.7. 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
	MLPH	NM_024101.7	MANE Select	c.180C>T	p.Asn60Asn	synonymous	Exon 3 of 16	NP_077006.1	Q9BV36-1
	MLPH	NM_001042467.3		c.180C>T	p.Asn60Asn	synonymous	Exon 3 of 15	NP_001035932.1	Q9BV36-2
	MLPH	NM_001281473.2		c.180C>T	p.Asn60Asn	synonymous	Exon 3 of 13	NP_001268402.1	Q9BV36-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLPH	ENST00000264605.8	TSL:1 MANE Select	c.180C>T	p.Asn60Asn	synonymous	Exon 3 of 16	ENSP00000264605.3	Q9BV36-1
	MLPH	ENST00000338530.8	TSL:1	c.180C>T	p.Asn60Asn	synonymous	Exon 3 of 15	ENSP00000341845.4	Q9BV36-2
	MLPH	ENST00000409373.5	TSL:1	c.180C>T	p.Asn60Asn	synonymous	Exon 3 of 13	ENSP00000386780.1	Q9BV36-3

Frequencies

GnomAD3 genomes AF: 0.00734 AC: 1117 AN: 152214 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00429

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0245

Gnomad SAS AF: 0.0497

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.0164 AC: 4112 AN: 251178 AF XY: 0.0174

Gnomad AFR exome AF: 0.00425

Gnomad AMR exome AF: 0.0302

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0275

Gnomad FIN exome AF: 0.0235

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.00666 AC: 9734 AN: 1461418 Hom.: 260 Cov.: 31 AF XY: 0.00788 AC XY: 5732 AN XY: 727012

African (AFR) AF: 0.00373 AC: 125 AN: 33478

American (AMR) AF: 0.0291 AC: 1303 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0326 AC: 1293 AN: 39698

South Asian (SAS) AF: 0.0537 AC: 4632 AN: 86258

European-Finnish (FIN) AF: 0.0235 AC: 1244 AN: 52958

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000551 AC: 613 AN: 1112010

Other (OTH) AF: 0.00844 AC: 510 AN: 60392

GnomAD4 genome AF: 0.00734 AC: 1118 AN: 152332 Hom.: 18 Cov.: 33 AF XY: 0.00941 AC XY: 701 AN XY: 74482

African (AFR) AF: 0.00428 AC: 178 AN: 41580

American (AMR) AF: 0.0149 AC: 228 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0245 AC: 127 AN: 5180

South Asian (SAS) AF: 0.0500 AC: 241 AN: 4824

European-Finnish (FIN) AF: 0.0256 AC: 272 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 68034

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00262 Hom.: 3

Bravo AF: 0.00625

Asia WGS AF: 0.0440 AC: 151 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.4
DANN	Benign	0.72
PhyloP100		-4.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2292878; hg19: chr2-238419286; COSMIC: COSV52820024; COSMIC: COSV52820024;